Piperazine compounds and medicinal use thereof

ABSTRACT

The present invention relates to a piperazine compound of the formula                    
     wherein R 1  and R 2  are each hydrogen, halogen, lower alkyl, lower alkoxy, amino, substituted amino, nitro, hydroxy or cyano, R 3 , R 4  and R 5  are each hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, substituted amino or hydroxy, R 6  and R 7  are each hydrogen, lower alkyl, lower alkyl substituted by halogen, aralkyl, acyl or lower acyl substituted by halogen, R 8  and R 9  are each hydrogen or lower alkyl, Y is lower alkylene and the like, and ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl, a pharmaceutically acceptable salt thereof and pharmaceutical agents containing these compounds. The compound of the present invention has superior TNF-α production inhibitory effect and/or IL-10 production promoting effect, and, since it is free of or shows only strikingly reduced expression of an effect on the central nervous system, the compound is useful as a highly safe and superior TNF-α production inhibitor an/or IL-10 production promoter and is useful as an agent for the prophylaxis or treatment of various diseases caused by abnormal TNF-α production, diseases curable with IL-10, such as chronic inflammatory diseases, acute inflammatory diseases, inflammatory diseases due to infection, autoimmune diseases, allergic diseases, and TNF-α mediated diseases.

TECHNICAL FIELD

The present invention relates to a pharmaceutical agent, particularly, apiperazine compound useful as a TNF-α production inhibitor and/or anIL-10 production promoter, and use thereof as a pharmaceutical agent.

BACKGROUND ART

There are a number of cytokines that have been found as proteinsinvolved in the expression of biological functions, such as biologicalimmune responses, inflammatory reactions and the like. Of suchcytokines, tumor necrosis factor alpha (hereinafter to be referred to asTNF-α) was first found as a cytokine having an anti-tumor effect.Subsequent studies have characterized it as a cytokine involved ininflammations. In recent years, TNF-α has been recognized as a cytokinebroadly involved in biophylaxis through inflammation and immuneresponses.

For example, TNF-α has been reported to show a promoting effect on theproduction of interleukin-1 (hereinafter to be referred to as IL-1),which is an inflammatory cytokine, and the like, an endotoxin shockinduction effect, a fibroblast proliferation effect, a bone resorptioneffect, and an action to cause arthritis, such as cartilage destructioneffect and the like [Beutler, B., et al., Nature, 316, 552-554(1985):Peetre, C., et al., J. Clin. Invest., 78, 1694-1700(1986):Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989)].

In rheumatoid arthritis, TNF-α activity has been found in synovial fluidand sera [Macnaul, K. L., et al., J. Immunol., 145, 4154-4166(1990):Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992)]. Sincean anti-TNF-α chimera antibody has been recently reported to beeffective against rheumatoid arthritis and Crohn's disease, theimportance of TNF-α in these diseases has been recognized [Elliott, M.J, et al., Arthritis Rheum., 36, 1681-1690 (1993):VanDullemen, H. M. etal., Gastroenterology 109, 129-135 (1995)].

Increased TNF-α concentrations have been reported in the expectorationof patients with adult respiratory distress syndrome (ARDS), which is aserious respiratory disease, and TNF-α is considered to be involved inARDS [Marks, J. D. et al., Am. Rev. Respir. Dis. 141, 94-97 (1990),Millar, A. B. et al., Nature, 324, 73 (1986)]. TNF-α is also consideredto be involved in viral hepatitis and fulminant viral hepatitis [Sheron,N. et al., Lancet 336, 321-322 (1990), Muto, Y. et al., Lancet, ii,72-74 (1986)].

In the case of myocardial ischemia, such as acute myocardial infarction,the TNF-α concentration in blood has been reported to increase [Latini,R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1990)], therebysuggesting the involvement of TNF-α in such disease state [Squadrito, F.et al., Inflammation Res., 45, 14-19 (1996), Lefer, A. M. et al.,Science, 249, 61-64 (1990)]. More recently, TNF-α has been reported toinhibit myocardial contraction [Finkel, M. S., et al., Science, 257,387-389 (1992); Pagani, D. F., et al., J. Clin. Invest., 90, 389-398(1992)].

In addition, TNF-α has been found to be equivalent to cachectin which isa cachexia inducer that hypercatabolizes the systemic metabolism incancer and infectious diseases and causes utmost exhaustion [B. Beutler,D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985)].

TNF-α is listed as one of the causes of sepsis [Starnes, H. F. Jr. etal., J. Immunol., 145, 4185-4191 (1990), Lechner, A. J. et al., Am. J.Physiol., 263, 526-535 (1992)], and an inhibitory effect on septic shockhas been acknowledged in an experiment using a TNF-α antibody [Starnes,H. F. Jr., et al., J. Immunol., 145, 4185-4191 (1990); Beutler, B., etal., Science, 229, 869-871 (1985)].

Other than the above-mentioned, possible involvement of TNF-α has beensuggested in osteoarthritis [Lewis, A. J. et al., Immunopharm.Immunotoxicol., 17, 607-613 (1995), Venn, G., et al., Arthritis Rheum.,36(6), 819-826 (1993)], multiple sclerosis [Sharief, M. K., etal., Engl.J. Med., 325(7), 467-472 (1991), Beck, J. et al., Acta. Neurol. Scand.,78, 318-323 (1988), Franciotta, D. M. et al., Ann. Neurol., 26, 787-789(1989), Hofmann, F. M. et al., J. Exp. Med., 170, 607-612 (1989), Gallo,P. et al., J. Neuroimmunol., 23, 41-44 (1989)], Kawasaki disease[Matsubara, T., et al., Clin. Immunol., Immunopathol., 56, 29-36(1990)], inflammatory bowel diseases such as ulcerative colitis, Crohn'sdisease and the like [Murch, S. et al., Arch. Dis. Child, 66, 561(1991), Van Dullemen et al., Gastroenterology, 109, 129-135 (1995)],Behqet's disease [Akoglu, T., et al., J. Rheumatol., 17,1107-1108(1990)], systemic lupus erythematosus (SLE) [Maury, C. P. J.,et al., Arthritis Rheum., 32, 146-150(1989)], graft versus host disease(GvHD) [Piruet et al., J. Exp. Med., 170, 655-663 (1987), Holler et al.,Blood, 75, 1011-1016 (1990), Irle et al., Bone Marrow Transplant., 3,127 (1988), Symington et al., Transplantation, 50, 518-521 (1990), Herveet al., Blood, 79, 3362-3368 (1992), Herve et al., Immunol. Rev., 129,31-55 (1992), Nestel, F. P., et al., J. Exp. Med., 175, 405-413 (1992)],allograft rejection [Imagawa et al., Transplantation, 50, 189-193(1990)], malaria [Grau, G. E., et al., Science, 237, 1210-1212 (1987),Grau et al., N. Engl. J. Med., 320, 1586-1591 (1989), Kwiatkowski etal., Q. J. Med., 86, 91-98 (1993)], acquired immunodeficiency syndrome(AIDS) [Lahdevirt et al., Am. J. Med., 85, 289-291 (1988), Tracy,Cancer. Cell, 1, 62-63 (1989), odeh, J. Intern. Med., 228, 549-556(1990), Bromberg et al., J. Immunol., 148, 3412-3417 (1992), Wllaurie etal., AIDS, 6, 1265-1268 (1992), Ayehunie et al., Clin. Exp. Immunol.,91, 37-42 (1993)], meningitis [Waage, A., et al., Lancet I,355-357(1987) diabetes [Held, W. et al., Proc. Natl. Acad. Sci. USA, 87,2239-2243 (1990), Hotamisligil, G. S., et al., Science, 259, 87-91(1993)], thermal burn [Marano, M. A. et al., Surg. Gynecol. Obstet.,170, 32-38 (1990)], ischemia-reperfusion injury [Squadrito, F. et al.,J. Lipid Mediators 8, 53-65 (1993)], chronic heart failure [Levine, B.et al., New Engl. J. Med., 323, 236-241 (1990)], infection [Chang etal., Immunol. Infect. Dis., 2, 61-68 (1992), Harvell, J. Immunol., 143,2894-2899 (1989), Kindler et al., Cell, 56,731-740 (1989), Liew et al.,Immunology, 69, 570-573 (1990), Nakane et al., Infect. Immun., 57,3331-3337 (1989), Nakano et al., J. Immunol., 144, 1935-1941 (1990),Opal etal., J. Infect. Dis., 161, 1148-1152 (1990)], contact dermatitis[Piguet et al., J. Exp. Med., 173, 673-679 (1991)], bacterial shock[Exley et al., Lancet, 335, 1275-1277 (1990)], endotoxemia [Beutler etal., Science, 229, 860-871 (1985)], demyelinating disease [Probert etal., Proc. Natl. Acad. Sic. U.S.A., 92, 11294-11298 (1995)], fibroidlung [Piguet et al., J. Exp. Med., 170, 655-663 (1989), Piguet et al.,Nature, 344, 245-247 (1990)], osteoporosis [Ishimi et al., J. Immunol.,145, 3297-3303 (1990), MacDonald et al., Br. J. Rheumatol., 31, 149-155(1992)], thrombus due to disseminated intravascular coagulation (DIC)and the like [Tracy et al., Surg. Gen. Obstet., 164, 415-422 (1987), Vanet al., N. Engl. J. Med., 322, 1622-1629 (1990)] and the like.

Interleukin-10 (hereinafter to be referred to as IL-10) is a cytokinemainly produced by type 2 helper T cells. IL-10 potentiates activity ofB cells and mast cells, but for macrophages, it is one of the inhibitorycytokines that strongly inhibit the function of type 1 helper T cellinvolved in cellular immunity, because they inhibit antigen presentingability or cytokine (TNF-α, IL-1 and the like) production capability ofmacrophages. Thus, IL-10 plays an important role in the immune responsesystem. For example, IL-10 has been reported to inhibit TNF-α productionby joint synovial cells in rheumatoid arthritis [Isomaki, P, et al.,Arthritis Rheum., 39, 386-395 (1996)]. It has been also reported that,when IL-10 is intravenously injected to a healthy subject and hemocytesof the subject are stimulated by endotoxin, TNF-α production isinhibited [Chernoff, A.E, et al., J. Immunol., 154, 5492-5499 (1995)].Moreover, a report has been documented that, in IL-10 gene knockoutmice, chronic colitis spontaneously occurs and, when compared to normalmice, inflammatory cytokine (TNF-α, IL-1 and the like) concentration incolon tissue significantly increases, but that administration of IL-10inhibits incidence of colitis and progress of the disease [Breg D. J. etal., J. Clin. Invest., 98, 1010 (1996)]. In the tumor cells, into whichIL-10 gene has been transferred, the tumor growth can be inhibited andmetastasis of the tumor can be also inhibited [Kundu N. et al., Int. J.Cancer, 76, 713 (1998)]. At present, a gene recombinant human IL-10 hasbeen under development as a therapeutic drug of septic shock, Crohn'sdisease, rheumatoid arthritis and malignant tumor.

JP-A-52-156879 discloses a piperazine derivative useful as an analgesicand antiphlogistic agent, psychotropic, antianxiety drug and hypotensiveagent, and JP-A-9-208570 discloses a benzylpiperazine derivative usefulas an anti-allergic agent and anti-inflammatory agent. U.S. Pat. No.5,569,659 discloses a 4-arylpiperazine compound and a 4-arylpiperidinecompound useful as an antipsychotic drug, and J. Med. Chem., vol. 38,pp. 4211-4222 (1995) discloses an N-aryl-N′-benzylpiperazine compoundwhich is useful as an antipsychotic drug. Moreover, WO92/12154 disclosesan imidazotriazine compound, and WO94/19350 discloses a pyrazolotriazinecompound, respectively as an IL-1 and TNF-α production inhibitor.

As mentioned above, it has become clear that hyperproduction of TNF-αcauses intense effect on normal cells and various disease states. Thus,a TNF-α production inhibitor that can cure such disease states has beendesired. However, the anti-TNF-α antibody currently under development isassociated with therapeutic problems such as availability only as aninjection, easy generation of antibody and the like, and therefore, itis not entirely satisfactory as a TNF-α production inhibitor.

A pharmaceutical agent that promotes the production of IL-10 is expectedto be a therapeutic agent of the diseases in which TNF-α is involved,because IL-10 inhibits production of TNF-α. However, such pharmaceuticalagent is not commercially available at the moment. A gene recombinanthuman IL-10 now being developed is a biological preparation, which issubject to therapeutic problems such as availability only as aninjection, easy generation of antibody and the like, as in the case ofanti-TNF-α antibody, and therefore, it is insufficient.

The compound disclosed in the above-mentioned JP-A-52-156879 has loweralkylene between phenyl and piperazine ring wherein the lower alkylenemay be methylene, ethylene, propylene, trimethylene or ethylidene.Specific examples include only the compounds wherein lower alkylene isethylene or propylene. These disclosed compounds have an analgesic andantiphlogistic effect but simultaneously have an effect on the centralnervous system. Because of the side effects due to the effect on thecentral nervous system, the development of the compound as an analgesicor antiphlogistic agent is difficult. In addition, the compoundsdisclosed in WO92/12154 and WO94/19350 do not show sufficient TNF-αproduction inhibitory effect, and are not satisfactory.

It is therefore an object of the present invention to provide a compoundwhich has a superior TNF-α production inhibitory effect and/or IL-10production promoting effect, has no effect on the central nervoussystem, and which is useful for the prophylaxis or treatment ofautoimmune diseases, inflammatory diseases and the like.

The present inventors have conducted intensive studies with the purposeof solving the above-mentioned problems and found that, of the compoundsdescribed in JP-A-52-156879, a compound wherein lower alkylene betweenphenyl and piperazine ring is methylene or methylene substituted bylower alkyl, which compound is not concretely disclosed therein, hassuperior TNF-α production inhibitory effect and/or IL-10 productionpromoting effect and is free of or shows only strikingly reducedexpression of an effect on the central nervous system, which resulted inthe completion of the present invention.

DISCLOSURE OF THE INVENTION

Accordingly, the present invention provides the following.

(1) A piperazine compound of the formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono- or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

R³, R⁴ and R⁵ are the same or different and each is hydrogen, halogen,lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- ordi-substituted by a group selected from the group consisting of loweralkyl and lower acyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s);

R⁸ and R⁹ are the same or different and each is hydrogen or lower alkyl;

Y is a group of the formula

wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen orlower alkyl, R¹² and R¹³ are the same or different and each is hydrogenor lower alkyl, or R¹² and R¹³ in combination form alkylene, R¹⁴ and R¹⁵are the same or different and each is hydrogen or lower alkyl, m is aninteger

of 0-2, n is an integer of 0-2, and 0≦m+n≦2; and ring A is phenyl,pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl,

provided that when one of R⁶ and R⁷ is hydrogen and the other is butyl,in Y, both R¹² and R¹³ are hydrogen, m and n are 0, R¹, R², R⁸ and R⁹are hydrogen, and ring A is phenyl, one of R³, R⁴ and R⁵ should not be2-isopropoxy and the remaining two should not be hydrogen,

and a pharmaceutically acceptable salt thereof.

(2) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono- or di-substituted by a groupselected from the group consisting of lower alkyl. and lower acyl,nitro, hydroxy or cyano;

R³, R⁴ and R⁵ are the same or different and each is hydrogen, halogen,lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- ordi-substituted by a group selected from the group consisting of loweralkyl and lower acyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s); and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

provided that when one of R⁶ and R⁷ is hydrogen and the other is butyl,in Y¹, both R¹² and R¹³ are hydrogen and R¹ and R² are hydrogen, one ofR³, R⁴ and R⁵ should not be 2-isopropoxy and the remaining two shouldnot be hydrogen,

and a pharmaceutically acceptable salt thereof.

(3) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono- or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

R³, R⁴ and R⁵ are the same or different and each is hydrogen, halogen,lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-ordi-substituted by a group selected from the group consisting of loweralkyl and lower acyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s);

R^(8a) is lower alkyl; and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

and a pharmaceutically acceptable salt thereof.

(4) The piperazine compound of the above-mentioned (3), wherein-R^(8a)is methyl and a pharmaceutically acceptable salt thereof.

(5) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono-or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

R³, R⁴ and R⁵ are the same or different and each is hydrogen, halogen,lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-ordi-substituted by a group selected from the group consisting of loweralkyl and lower acyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s);

R^(8a) and R^(9a) are the same or different and each is lower alkyl; and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

and a pharmaceutically acceptable salt thereof.

(6) The piperazine compound of the above-mentioned (5), wherein R^(8a)and R^(9a) are both methyl, and a pharmaceutically acceptable saltthereof.

(7) The piperazine compound of any of the above-mentioned (1) to (6),wherein R³, R⁴ and R⁵ are the same or different and each is hydrogen,halogen or lower alkoxy, and a pharmaceutically acceptable salt thereof.

(8) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono-or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by agroup selected from the group consisting of lower alkyl and lower acyl,and R¹⁸ is hydrogen or lower alkyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s); and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

and a pharmaceutically acceptable salt thereof.

(9) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono- or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino mono- or di-substituted by agroup selected from the group consisting of lower alkyl and lower acyl,and R¹⁸ is hydrogen or lower alkyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s);

R^(8a) is lower alkyl; and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

and a pharmaceutically acceptable salt thereof.

(10) The piperazine compound of the above-mentioned (9), wherein R^(8a)is methyl, and a pharmaceutically acceptable salt thereof.

(11) The piperazine compound of the above-mentioned (1), which has thefollowing formula

wherein

R¹ and R² are the same or different and each is hydrogen, halogen, loweralkyl, lower alkoxy, amino, amino mono- or di-substituted by a groupselected from the group consisting of lower alkyl and lower acyl, nitro,hydroxy or cyano;

ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,

halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by agroup selected from the group consisting

of lower alkyl and lower acyl, and R¹⁸ is hydrogen or lower alkyl;

R⁶ and R⁷ are the same or different and each is hydrogen, lower alkyl,lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or loweracyl substituted by 1 to 3 halogen(s);

R^(8a) and R^(9a) are the same or different and each is lower alkyl; and

Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene,

and a pharmaceutically acceptable salt thereof.

(12) The piperazine compound of the above-mentioned (11), wherein R^(8a)and R^(9a) are both methyl, and a pharmaceutically acceptable saltthereof.

(13) The piperazine compound of any of the above-mentioned (1) to (12),wherein one of R⁶ and R⁷ is hydrogen and the other is acyl, and apharmaceutically acceptable salt thereof.

(14) The piperazine compound of any of the above-mentioned (1) to (13),wherein R¹² and R¹³ are the same or different and each is hydrogen ormethyl, R¹² and R¹³ in combination form ethylene, and a pharmaceuticallyacceptable salt thereof.

(15) The piperazine compound of the above-mentioned (1), (2), (7), (13)or (14), which is a member selected from the group consisting ofN-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide,N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-ethyl)acetamide,N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide,N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)-acetamideandN-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide,

and a pharmaceutically acceptable salt thereof.

(16) The piperazine compound of the above-mentioned (1), (3), (4), (7),

(13) or (14), which is a member selected from the group consisting ofN-(4-(1-( 4-phenylpiperazin-1-yl) ethyl)phenylmethyl )acetamide,N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamideandN-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide,

and a pharmaceutically acceptable salt thereof.

(17) The piperazine compound of the above-mentioned (1), (5)-(7), (13)or (14), which isN-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl) phenylmethyl)acetamide, and a pharmaceutically acceptable salt thereof.

(18) The piperazine compound of the above-mentioned (1), (7), (8), (13)or (14), which is a member selected from the group consisting ofN-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide,N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-formamide,N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-propionamide,N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide andN-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide,

and a pharmaceutically acceptable salt thereof.

(19) The piperazine compound of the above-mentioned (1), (7), (9), (10),(13) or (14), which isN-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide,and a pharmaceutically acceptable salt thereof.

(20) A pharmaceutical composition containing the piperazine compound ofany of the above-mentioned (1) to (19) or a pharmaceutically acceptablesalt thereof as an active ingredient.

(21) A TNF-α production inhibitor and/or IL-10 production promotercontaining the piperazine compound of any of the above-mentioned (1) to(19) or a pharmaceutically acceptable salt thereof as an activeingredient.

(22) An agent for the prophylaxis or treatment of diseases caused byabnormal TNF-α production, TNF-α mediated diseases or diseases curablewith IL-10, which contains the piperazine compound of any of theabove-mentioned (1) to (19) or a pharmaceutically acceptable saltthereof as an active ingredient.

(23) An agent for the prophylaxis or treatment of an inflammatorydisease, which contains the piperazine compound of any of theabove-mentioned (1) to (19) or a pharmaceutically acceptable saltthereof as an active ingredient.

(24) An agent for the prophylaxis or treatment of an autoimmune disease,which contains the piperazine compound of any of the above-mentioned (1)to (19) or a pharmaceutically acceptable salt thereof as an activeingredient.

(25) An agent for the prophylaxis or treatment of rheumatoid arthritis,which contains the piperazine compound of any of the above-mentioned (1)to (19) or a pharmaceutically acceptable salt thereof as an activeingredient.

(26) An agent for the prophylaxis or treatment of an allergic disease,which contains the piperazine compound of any of the above-mentioned (1)to (19) or a pharmaceutically acceptable salt thereof as an activeingredient.

The groups shown by respective symbols in the specification areexplained in the following.

Halogen at R¹ and R² is fluorine, chlorine, bromine or iodine.

Lower alkyl at R¹ and R² is alkyl having 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike.

Lower alkoxy at R¹ and R² is alkoxy having 1 to 4 carbon atoms, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

With regard to the amino mono- or di-substituted by a group selectedfrom lower alkyl and lower acyl at R¹ and R², lower alkyl as asubstituent means alkyl having 1 to 4 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbonatoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C₁-C₄ loweralkanoyl substituted by phenyl. Examples thereof include formyl, acetyl,propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. Aminomono- or di-substituted by these substituents means methylamino,dimethylamino, ethylamino, diethylamino, propylamino, butylamino,acetylamino, diacetylamino, propionylamino, dipropionylamino,butyrylamino, N-methyl-N-acetylamino, N-ethyl-N-acetylamino,N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, tert-butoxycarbonylamino, benzoylamino,phenylacetylamino and the like.

Halogen at R³, R⁴ and R⁵ is fluorine, chlorine, bromine or iodine.

Lower alkyl at R³, R⁴and R⁵ means alkyl having 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike.

Lower alkoxy at R³, R⁴ and R⁵ means alkoxy having 1 to 4 carbon atoms,such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy andthe like.

With regard to the amino mono- or di-substituted by a group selectedfrom lower alkyl and lower acyl at R³, R⁴ and R⁵, lower alkyl as asubstituent means alkyl having 1 to 4 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbonatoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C₁-C₄ loweralkanoyl substituted by phenyl. Examples thereof include formyl, acetyl,propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. Theamino mono- or di-substituted by these substituents may be methylamino,dimethylamino, ethylamino, diethylamino, propylamino, butylamino,acetylamino, diacetylamino, propionylamino, dipropionylamino,butyrylamino,- N-methyl-N-acetylamino, N-ethyl-N-acetylamino,N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, tert-butoxycarbonylamino, benzoylamino,phenylacetylamino and the like.

Lower alkyl at R⁶ and R⁷ means alkyl having 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike.

The lower alkyl substituted by 1 to 3 halogen(s) at R⁶ and R⁷ is

C₁-C₄ lower alkyl substituted by halogen (e.g., fluorine, chlorine,bromine and the like). Examples thereof include fluoromethyl,trifluoromethyl, chloromethyl, bromomethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl,3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl and the like.

Aralkyl at R⁶ and R⁷ means benzyl, 2-phenylethyl, 3-phenylpropyl.

Acyl at R⁶ and R⁷ means alkanoyl having 1 to 5 carbon atoms, loweralkoxycarbonyl having 1 to 4 carbon atoms, C₁-C₄ lower alkanoylsubstituted by phenyl or pyridyl, or C₁-C₄ lower alkylsulfonyl. Examplesthereof include formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl,trimethylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, benzoyl, nicotinoyl, isonicotinoyl, picolinoyl,phenylacetyl, phenylpropionyl, methanesulfonyl and the like.

Lower acyl substituted by 1 to 3 halogen(s) at R⁶ and R⁷ is C₁-C₄ loweracyl substituted by halogen (e.g., fluorine, chlorine, bromine and thelike). Examples thereof include fluoroacetyl, trifluoroacetyl,chloroacetyl, bromoacetyl, 3-chloropropionyl, 3-bromopropionyl,4-chlorobutyryl, 4-bromobutyryl and the like.

Lower alkyl at R⁸ and R⁹ means alkyl having 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl and the like.

Lower alkyl at R¹⁰ and R¹¹ means alkyl having 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl and the like.

Lower alkyl at R¹² and R¹³ means alkyl having 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl and the like.

The alkylene formed by R¹² and R¹³ in combination means methylene,ethylene, trimethylene, tetramethylene, pentamethylene.

Lower alkyl at R¹⁴ and R¹⁵ means alkyl having 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl and the like.

Halogen at R¹⁶ and R¹⁷ means fluorine, chlorine, bromine or iodine.

Lower alkyl at R¹⁶ and R¹⁷ means alkyl having 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike. Lower alkoxy at R¹⁶ and R¹⁷ means alkoxy having 1 to 4 carbonatoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxyand the like.

With regard to the amino mono- or di-substituted by a group selectedfrom lower alkyl and lower acyl at R¹⁶ and R¹⁷, lower alkyl as asubstituent means alkyl having 1 to 4 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbonatoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C₁-C₄ loweralkanoyl substituted by phenyl. Examples thereof include formyl, acetyl,propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. Theamino mono- or di-substituted by these substituents is exemplified bymethylamino, dimethylamino, ethylamino, diethylamino, propylamino,butylamino, acetylamino, diacetylamino, propionylamino,dipropionylamino, butyrylamino, N-methyl-N-acetylamino,N-ethyl-N-acetylamino, N-methyl-N-propionylamino, methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino,benzoylamino, phenylacetylamino and the like.

Lower alkyl at R¹⁸ means alkyl having 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike.

Ring A is

wherein each symbol is as defined in the above. Ring A′ is 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazyl or 2-imidazolyl, mentionedabove, with preference given to the above-mentioned 2-pyrimidyl,2-thiazolyl, 2-pyridyl or 2-imidazolyl.

The pharmaceutically acceptable salt of the compound (I) of the presentinvention is, for example, a salt with inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid and the like, a salt with organic acid suchas acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid,succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonicacid and the like. The compound of the present invention can beconverted to a quaternary ammonium salt. The compound of the presentinvention (I) and a pharmaceutically acceptable salt thereof may be ahydrate (monohydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate,3/2 hydrate, 3/4 hydrate and the like) or a solvate. When the inventivecompound (I) has an asymmetric carbon, at least two optical isomersexist. The present invention encompasses these optical isomers andracemates thereof.

The compound of the present invention can be produced by, for example,the following methods.

Method A

wherein Lv is a leaving group widely used in the organic syntheticchemistry, suchas halogen (e.g, fluorine, chlorine, bromineor iodine),mnethanesulfonyloxy, p-toluenesulfonyloxy andtrifluoromethane-sulfonyloxy, P¹ and P² encompass R⁶ and R⁷ definedearlier, and further mean an amino-protecting group widely used in theorganic synthetic chemistry, such as benzyloxycarbonyl, P¹and P² mayform an imido group, such as phthalimide, together with the adjacentnitrogen atom and other symbols are as defined above. When R³, R⁴ and R⁵have a functional group such as amino, hydroxy and the like, they may beprotected as necessary.

The base to be used for the condensation of compound (II) and compound(III) may be, for example, potassium carbonate, potassiumhydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodiumhydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassiumhydride, lithium diisopropylamide, butyl lithium, lithiumhexamethyldisilazane, triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine and4-dimethylaminopyridine.

The solvent to be used for the condensation may be, for example,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene,hexane, dimethylformamide, dimethyl sulfoxide, water and a mixturethereof.

The reaction temperature of condensation is generally from −80° C. to150° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

After condensation under the above-mentioned reaction conditions, aprotecting group(s) is/are removed as necessary, after which compound(I) can be purified by a method known in the field of organic syntheticchemistry, such as solvent extraction, recrystallization,chromatography, and a method using an ion exchange resin.

The compound (III) may be a commercially available one or may besynthesized from bis(2-chloro or bromoethyl)amine and substitutedaromatic amine according to the method disclosed in Journal of MedicinalChemistry (J. Med. Chem.), vol. 29, pp. 630-634 (1986) or TetrahedronLetters, vol. 37, pp. 319-322 (1996). Alternatively, it can besynthesized by treating bis(2-hydroxyethyl)amine and substitutedaromatic amine in an aqueous hydrochloric acid solution.

Method B

Compound (I) wherein one of R⁶ and R⁷ is acyl and the other is hydrogenis hydrolyzed to give compound (I-1) wherein R⁶ and R⁷ of compound (I)are hydrogen

wherein each symbol is as defined above.

Hydrolysis can be performed under both acidic conditions and basicconditions. When acidic conditions are employed, mineral acid (e.g.,hydrochloric acid, sulfuric acid and the like), preferably aconcentrated or diluted aqueous hydrochloric acid solution, is used and,Cas an organic co-solvent, for example, methanol, ethanol, tert-butylalcohol, tetrahydrofuran, ethylene glycol dimethyl ether,dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereofis used. When basic conditions are employed, the base to be used may be,for example, sodium hydroxide, potassium hydroxide, lithium hydroxide orbarium hydroxide. The solvent used may be, for example, water, methanol,ethanol, tert-butyl alcohol, tetrahydrofuran, dimethylformamide,dimethyl sulfoxide, acetonitrile or a mixture thereof.

The reaction temperature of hydrolysis is generally from −20° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of hydrolysis is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

After hydrolysis under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (I-1) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

The methods (Method B1 to Method B8) for modifying the amino group ofcompound (I-1) are explained in the following.

Method B1

wherein R^(a) is C₁-C₄ alkyl optionally substituted by 1 to 3 halogen(s)(e.g., fluorine, chlorine, bromine and the like), Hal is halogen (e.g.,chlorine, bromine, iodine and the like), R^(b) is C₁-C₄ alkyl optionallysubstituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine andthe like), R^(c) is C₁-C₄ alkyl optionally substituted by 1 to 3halogen(s) (e.g., fluorine, chlorine, bromine and the like), and theother symbols are as defined above.

The base to be used for condensation of compound (I-1) may be, forexample, triethylamine, diisopropylethylamine, potassiumcarbonate,potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate,sodium hydroxide, sodiummethoxide, sodium ethoxide, pyridine and4-dimethylaminopyridine.

The solvent to be used for condensation may be, for example, water,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,benzene, dichloromethane, dichloroethane, chloroform, ethyl acetate,toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide and amixture thereof.

The reaction temperature of condensation is generally from −20° C. to80° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-2) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B2

wherein each symbol is as defined above.

The reducing agent to be used for reduction of amide group in compound(I-2) may be, for example, metallic reducing reagent such as aluminumlithium hydride, sodium borohydride, lithium borohydride and the like,or diborane.

The solvent to be used for reduction of amide group may be, for example,tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol,2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, amixture thereof and the like.

The reaction temperature of reduction of amino group is generally from−20° C. to 80° C., and a temperature above or under this range can beemployed as necessary.

The reaction time of reduction of amide group is generally from 30minutes to 10 hours, and a time longer or shorter than this range can beemployed as necessary.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-3) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B3

Compound (I-3) can be also produced by the following method.

wherein each symbol is as defined above.

The reducing agent to be used for reductive amination of compound (I-1)may be, for example, sodium borohydride or sodium cyanoborohydride, andcatalytic reduction using transition metal (e.g., palladium-carbon,platinum oxide, Raney nickel, rhodium, ruthenium) is also effective.

The solvent to be used for reductive amination may be, for example,water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,acetone, ethyl acetate, acetic acid, benzene, toluene, xylene,dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of reductive amination is generally from −20°C. to 150° C., and a temperature above or under this range can beemployed as necessary.

The reaction time of reductive amination is generally from 30 minutes to2 days, and a time longer or shorter than this range can be employed asnecessary.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-3) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B4

wherein R^(d) is hydrogen or C₁-C₄ alkyl optionally substituted by 1 to3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), and theother symbols are as defined above.

The reaction conditions (reagent, reaction solvent, reaction time) ofacylation are the same as in Method B1.

After acylation under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-4) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B5

wherein each symbol is as defined above.

The reaction conditions (reagent, reaction solvent, reaction time) ofreduction are the same as in Method B2.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-5) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin. Method B6

wherein R^(e) is C₁-C₄ alkyl optionally substituted by 1 to 3 halogen(s)(e.g., fluorine, chlorine, bromine and the like), and the other symbolsto are as defined above.

In this reaction, the acyl moiety (R^(c)—C═O) is preferablyelectron-withdrawing group such as trifluoroacetyl and the like.

The base to be used for condensation of compound (I-2) may be, forexample, sodium hydroxide, sodium methoxide, sodium ethoxide, sodiumhydride, potassium hydride, lithium diisopropylamide, butyl lithium,phenyl lithium, lithium hexamethyldisilazane, triethylamine,diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undeca-7-ene.

The solvent to be used for condensation may be, for example, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran,dioxane, diethyl ether, ethylene glycol dimethyl ether, dichloromethane,dichloroethane, chloroform, benzene, toluene, xylene, hexane,dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of condensation is generally from −80° C. to150° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

After condensation under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (I-6) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B7

wherein each symbol is as defined above.

Hydrolysis is performed under the same reaction conditions as in MethodB.

After hydrolysis under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (I-7) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method B8

wherein each symbol is as defined above.

The reduction is performed under the same reaction conditions as inMethod B2.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-5a) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method C

Compound (I) can be also produced by the following method.

wherein each symbol is as defined above.

The reaction conditions (reagent, reaction solvent, reaction time) ofcondensation are the same as in the condensation in Method A.

After condensation under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (I) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method D

Compound (I-1) can be also produced by the following method.

wherein each symbol is as defined above.

The metal azide compound to be used for the azidation of compound (VIII)is exemplified by sodium azide, lithium azide and the like.

The solvent to be used for azidation may be, for example, water,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,acetone, ethyl acetate, acetic acid, benzene, toluene, xylene,dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of azidation is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of azidation is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

The reducing agent to be used for reduction of the azide group incompound (X) may be, for example, a metallic reducing reagent such asaluminum lithium hydride, sodium borohydride, lithium borohydride,sodium cyanoborohydride and the like, diborane or triphenylphosphine,and catalytic reduction using transition metal (e.g., palladium-carbon,platinum oxide, Raney nickel, rhodium, ruthenium) is also effective.

The solvent to be used for reduction of the azide group may be, forexample, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butylalcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycoldimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene,xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of reduction of the azide group is generallyfrom −20° C. to 150° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the azide group is generally from 30minutes to 2 days, and a time longer or shorter than this range can beemployed as necessary.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method E

Compound (I-1) can be also produced by the following method.

wherein each symbol is as defined above.

The solvent to be used for condensation of compound (VIII) may be, forexample, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butylalcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycoldimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene,xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of condensation is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

The base to be used for cleavage of compound (XI) may be, for example,hydrazine hydrate, methyl hydrazine, phenyl hydrazine, sodium hydroxide,potassium hydroxide, barium hydroxide or lithium hydroxide.

The solvent to be used for cleavage may be, for example, water,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,acetone, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of cleavage is generally from 0° C. to 150° C.,and a temperature above or under this range can be employed asnecessary.

The reaction time of cleavage is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method F

Compound (XI) can be also produced by the following method.

wherein each symbol is as defined above.

The reagent to be used for Mitsunobu reaction may be, for example,dialkyl azodicarboxylate (wherein alkyl means lower alkyl such as ethyl,propyl, isopropyl, butyl, isobutyl and the like) and triphenylphosphine.

The solvent to be used for Mitsunobu reaction may be, for example,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,acetone, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of Mitsunobu reaction is generally from −80° C.to 100° C., and a temperature above or under this range can be employedas necessary.

The reaction time of Mitsunobu reaction is generally from 30 minutes to2 days, and a time longer or shorter than this range can be employed asnecessary.

After Mitsunobu reaction under the above-mentioned reaction conditionsand, where necessary, removal of protecting group(s), compound (XI) canbe purified by a method known in the field of organic syntheticchemistry, such as solvent extraction, recrystallization,chromatography, and a method using an ion exchange resin.

Method G

Compound (I) can be also produced by the following method.

wherein Q is the aforementioned leaving group, Lv and its precursorhydroxyl group with or without protection with a suitable protectinggroup, which can be easily converted to Lv by a method known in thefield of organic synthetic chemistry, and other symbols are as definedabove.

The reaction conditions of the condensation of compound (XIII) andcompound (IX) are the same as in the conditions for Method C, Method Dand Method E. The group Q of the obtained compound (XIV) is converted toa leaving group Lv as necessary by a method known in the field oforganic synthetic chemistry, and condensed with compound (III) in thesame manner as in Method A, which is followed by, where necessary,removal of protecting group(s) to produce compound (I).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method H

Compound (I) can be also produced by the following method.

wherein each symbol is as defined above.

The reaction conditions of the condensation of compound (XV) andcompound (III) are the same as in the conditions for Method A. The groupQ of the obtained compound (XVI) is converted to a leaving group Lv by amethod known in the field of organic synthetic chemistry. Then, in thesame manner as in Method C, Method D and Method E, it is condensed withcompound (IX) and, where necessary, the protecting group(s) is/areremoved to produce compound (I).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method I

Compound (I) can be also produced by the following method.

wherein each symbol is as defined above.

The reaction conditions (reagent, reaction solvent, reaction time) ofcondensation of compound (II) and compound (XVII) are the same as inMethod A.

The group Q of the obtained compound (XVIII) is converted to a leavinggroup Lv as necessary by a method known in the field of organicsynthetic chemistry. In the same manner as in Method A, it is condensedwith compound (XIX) and, where necessary, the protecting group(s) is/areremoved to produce compound (I).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method J

Compound (I) can be also produced by the following method.

wherein each symbol is as defined above.

The reaction conditions (reagent, reaction solvent, reaction time) ofcondensation in this method are the same as in Method A.

After condensation under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (I) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

The compound (XXI) can be produced by condensing compound (XIX) withcompound (XXIIa)

wherein Q, Hal and R are as defined above, in the same manner as inMethod A to give compound (XXIIb) (wherein each symbol is as definedabove), and converting the group Q of compound (XXIIb) to a leavinggroup Lv as necessary by a method known in the field of organicsynthetic chemistry. The compound (XXIIb) can be produced by condensingcompound (XIX) with compound (XXIIc) (wherein R is lower alkyl having 1to 4 carbon atoms and Hal is as defined above) in the same manner as inMethod A to give compound (XXIId) (wherein each symbol is as definedabove), and converting the resulting compound by a method known in thefield of organic synthetic chemistry.

The reaction conditions (reagent, reaction solvent, reaction time) ofcondensation are the same as in Method A.

The reducing agent to be used for reduction of the ester group incompound (XXIId) may be, for example, a metallic reducing reagent suchas aluminum lithium hydride, sodium borohydride, lithium borohydride andthe like, or diborane.

The solvent to be used for reduction of the ester group may be, forexample, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol,1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethylether or a mixture thereof.

The reaction temperature of reduction of the ester group is generallyfrom −20° C. to 80° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the ester group is generally from 30minutes to 10 hours, and a time longer or shorter than this range can beemployed as necessary.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (XXIIb) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method K

Compound (I) can be also produced by the following method.

wherein L_(v1) is a leaving group widely used in aromatic nucleophilicsubstitution reaction, such as halogen (e.g., fluorine, chlorine,bromine or iodine), nitro, p-toluenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy, benzenesulfenyl, benzenesulfonyl, azido,aryloxy, alkoxy, alkylthio or amino, and the other symbols are asdefined above.

The solvent to be used for aromatic nucleophilic substitution reactionof compound (XXIII) may be, for example, methanol, ethanol, 1-propanol,2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether,ethylene glycol dimethyl ether, benzene, dichloromethane,dichloroethane, chloroform, toluene, xylene, hexane, dimethylformamide,dimethyl sulfoxide, acetonitrile or a mixture thereof.

For aromatic nucleophilic substitution reaction, a catalyst such ascopper powder, copper oxide and the like can be added as necessary.

The reaction temperature of aromatic nucleophilic substitution reactionis generally from 0° C. to 150° C., and a temperature above or underthis range can be employed as necessary.

The reaction time of aromatic nucleophilic substitution reaction isgenerally from 30 minutes to 2 days, and a time longer or shorter thanthis range can be employed as necessary.

After aromatic nucleophilic substitution reaction under theabove-mentioned reaction conditions and, where necessary, removal ofprotecting group(s), compound (I) can be purified by a method known inthe field of organic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Method L

Compound (II) wherein R⁸ and R⁹ are both hydrogen can be produced by thefollowing method.

wherein W is carboxylic acid derivative that can be easily converted toeach other by a method basic and widely used in the field of organicsynthetic chemistry, such as carboxylic acid, carboxylic acid ester(COOR; wherein R is lower alkyl having 1 to 4 carbon atoms), carboxamideor carbonitrile, and the other symbols are as defined above.

The compound (XXV) is converted to an ester group as necessary by amethod known in the field of organic synthetic chemistry and subjectedto reduction.

The reducing agent to be used for reduction of the ester group may be,for example, a metallic reducing reagent (e.g., aluminum lithiumhydride, sodium borohydride, lithium borohydride and the like) ordiborane.

The solvent to be used for reduction of the ester group may be, forexample, water, tetrahydrofuran, dioxane, diethyl ether, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycoldimethyl ether, a mixture thereof, and the like.

The reaction temperature of reduction of the ester group is generallyfrom −20° C. to 80° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the ester group is generally from 30minutes to 10 hours, and a time longer or shorter than this range can beemployed as necessary.

After reduction under the above-mentioned reaction conditions, thehydroxyl group of compound (XXVI) is converted to a group Lv by a methodknown in the field of organic synthetic chemistry, and where necessary,the protecting group(s) is/are removed. The compound (II-a) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

The compound (II-a) and compound (III) are condensed in the same manneras in Method A, and, where necessary, the protecting group(s) is/areremoved to give compound (I) wherein RB and R⁹ are both hydrogen,namely, compound (I-8)

wherein each symbol is as defined above.

Method M

Compound (XIV) wherein R⁸ is lower alkyl and R⁹ is hydrogen can beproduced by the following method.

wherein R^(8a) is lower alkyl, and the other symbols are as definedabove.

The acid catalyst used for Friedel-Crafts reaction of compound (XXVII)is, for example, aluminum chloride, aluminum bromide, titanium chloride,sulfuric acid, zinc chloride, iron chloride or hydrogen fluoride,phosphoric acid.

The solvent to be used for the Friedel-Crafts reaction may be, forexample, tetrahydrofuran, dioxane, diethyl ether, dichloromethane,dichloroethane, chloroform, ethylene glycol dimethyl ether,acetonitrile, nitromethane, carbon disulfide or a mixture thereof. Wherenecessary, the solvent may not be used.

The reaction temperature of the Friedel-Crafts reaction is generallyfrom −20 C. to 100° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the Friedel-Crafts reaction isgenerally from 30 minutes to 24 hours, and a time longer or shorter thanthis range can be employed as necessary.

The reducing agent to be used for reduction of the carbonyl group incompound (XXIX) may be, for example, a metallic reducing reagent such asaluminum lithium hydride, sodium borohydride, lithium borohydride andthe like, or diborane.

The solvent to be used for reduction of the carbonyl group may be, forexample, water, tetrahydrofuran, dioxane, diethyl ether, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycoldimethyl ether, a mixture thereof, and the like.

The reaction temperature of reduction of the carbonyl group is generallyfrom −20° C. to 80° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the carbonyl group is generally from30 minutes to 10 hours, and a time longer or shorter than this range canbe employed as necessary.

The obtained compound (XXX) is converted to a group Q by a method knownin the field of organic synthetic chemistry to produce compound (XIV-a).

The group Q of compound (XIV-a) is converted to a group Lv as necessaryby a method known in the field of organic synthetic chemistry andcondensed with compound (III) in the same manner as in Method A. Wherenecessary, the protecting group(s) is/are removed to produce compound(I) wherein R⁹ is hydrogen, namely, compound (I-9)

wherein each symbol is as defined above.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method N

Compound (II) wherein R⁸ and R⁹ are both hydrogen and Lv is particularlyhalogen can be produced by the following method.

wherein each symbol is as defined above.

The reagent to be used for halomethylation of compound (XXVII) isexemplified by formaldehyde and hydrogen chloride, formaldehyde andhydrogen bromide, formaldehyde and hydrogen iodide, chloromethyl methylether, bis(chloromethyl) ether, methoxyacetyl chloride and1-chloro-4-(chloromethoxy)butane.

The catalyst to be used for halomethylation is, for example, zincchloride, aluminum chloride, aluminum bromide, titanium chloride or ironchloride.

The solvent to be used for halomethylation may be, for example,tetrahydrofuran, dioxane, diethyl ether, dichloromethane,dichloroethane, chloroform, ethylene glycol dimethyl ether,acetonitrile, nitromethane, carbon disulfide or a mixture thereof.

The reaction temperature of halomethylation is generally from −20° C. to100° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of halomethylation is generally from 30 minutes to 24hours, and a time longer or shorter than this range can be employed asnecessary.

After halomethylation under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (II-b) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Moreover, compound (II-b) and compound (III) are condensed in the samemanner as in Method A to produce compound (I-8).

Method O

Compound (XXVI) can be also produced by the following method.

wherein each symbol is as defined above.

The Lewis acid to be used for the reaction with dichloromethyl methylether may be, for example, aluminum chloride, titanium tetrachloride,tin tetrachloride, antimony(v)chloride, iron(III) chloride, borontrifluoride, bismuth(III) chloride, zinc chloride, mercury(II) chlorideand the like.

The organic solvent to be used for the reaction with dichloromethylmethyl ether may be, for example, tetrahydrofuran, diethyl ether,ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide,methylene chloride, chloroform, dichloroethane, acetonitrile,nitromethane, carbon disulfide and the like. Where necessary, a solventmay not be used.

The temperature of reaction with dichloromethyl methyl ether isgenerally from −50° C. to 50° C., and a temperature above or under thisrange can be employed as necessary.

The time of reaction with dichloromethyl methyl ether is generally from30 minutes to 24 hours, and a time longer or shorter than this range canbe employed as necessary.

The reducing agent to be used for reduction of the formyl group incompound (XXXI) may be, for example, a metallic reducing reagent such asaluminum lithium hydride, sodium borohydride, lithium borohydride andthe like, or diborane.

The solvent to be used for reduction of the formyl group may be, forexample, water, tetrahydrofuran, dioxane, diethyl ether, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycoldimethyl ether, a mixture thereof, and the like.

The reaction temperature of reduction of the formyl group is generallyfrom −20° C. to 80° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the formyl group is generally from 30minutes to 10 hours, and a time longer or shorter than this range can beemployed as necessary.

The compound (XXVI) can be produced using a haloform reaction as the keyreaction.

The acylation of compound (XXVII) with acetyl chloride is performedunder the same reaction conditions as in Method M.

The reagent to be used for the haloform reaction of compound (XXIXa) maybe, for example, base (e.g., sodium hydroxide, potassium hydroxide andthe like), and a halogenating agent (e.g., bromine, chlorine, sodium(potassium) hypochlorite, sodium (potassium) hypobromite and the like).

The solvent to be used for haloform reaction may be, for example, water,methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane, a mixture thereof, and the like.

The temperature of haloform reaction is generally from −20° C. to 100°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of haloform reaction is generally from 30 minutes to24 hours, and a time longer or shorter than this range can be employedas necessary.

Conversion of compound (XXVa) via compound (XXVb) to compound (XXVI) isperformed under the reaction conditions described for Method L.

The compound (XXVa) can be also produced by directly from compound(XXVII) by Friedel-Crafts reaction using oxalyl chloride. TheFriedel-Crafts reaction using oxalyl chloride is performed under thereaction conditions described for Method M.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

The compound (XXXI) can be also produced from compound (XXVII) usingknown Friedel-Crafts type reaction widely used in the field of organicsynthetic chemistry, such as Gattermann-Koch method, Gattermann method,Vilsmeier method, Duff method.

Method P

The compound (XIV), compound (II-a), compound (XV) can be converted tocompound (XX) by introducing an amino group described in, for example,Method D, Method E and Method F.

Method Q

Compound (I-1) and compound (XII) wherein R⁸ and R⁹ are both hydrogencan be also produced by the following method.

wherein Y^(a) is single bond or alkyl having one less carbon atoms thanY defined above, A is hydroxy or amino, and the other symbols are asdefined above.

For condensation of compound (XXXII) and compound (III), for example, 1)acid chloride method and 2) mixed acid anhydride method widely used inthe field of organic synthetic chemistry are particularly effective.

The reagent used for the acid chloride method may be, for example,thionyl chloride and oxazolyl chloride.

The solvent to be used for acid chloride method may be, for example,tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether,benzene, dichloromethane, dichloroethane, chloroform, toluene, xyleneand hexane.

The reaction temperature of acid chloride method is generally from 0° C.to 80° C., and a temperature above or under this range can be employedas necessary.

The reaction time of acid chloride method is generally from 30 minutesto 2 days, and a time longer or shorter than this range can be employedas necessary.

The reagent used for the mixed acid anhydride method may be, forexample, methyl chlorocarbonate, ethyl chlorocarbonate, isopropylchlorocarbonate, isobutyl chlorocarbonate or phenyl chlorocarbonate.

The base to be used for mixed acid anhydride method may be, for example,triethylamine, diisopropylethylamine, potassium carbonate, potassiumhydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodiumhydroxide, sodium methoxide or sodium ethoxide.

The solvent to be used for acid anhydride method may be, for example,tetrahydrofuran, dioxane, acetone, diethyl ether, ethylene glycoldimethyl ether, benzene, dichloromethane, dichloroethane, chloroform,toluene, xylene or hexane.

The reaction temperature of mixed acid anhydride method is generallyfrom −80° C. to 20° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of acid anhydride method is generally from 30 minutesto 2 days, and a time longer or shorter than this range can be employedas necessary.

The reducing agent to be used for compound (XXXIII) may be, for example,a metallic reducing reagent (e.g., aluminum lithium hydide, sodiumborohydride, lithium borohydride and the like), or diborane.

The solvent to be used for reduction may be, for example, water,tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol,2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, amixture thereof, and the like.

The reaction temperature of reduction is generally from −20° C. to 80°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of reduction is generally from 30 minutes to 10 hours,and a time longer or shorter than this range can be employed asnecessary.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method R

Compound (I-1) can be also produced by the following method.

wherein each symbol is as defined above.

The compound (XXXV) and compound (III) are condensed under the samereaction conditions as in Method A.

The group Q of compound (XXXVI) is converted to a leaving group Lv asnecessary by a method known in the field of organic synthetic chemistryand then subjected to cyanation.

The reagent to be used for cyanation may be, for example, sodium cyanideor potassium cyanide.

The solvent to be used for cyanation may be, for example, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran,dimethylformamide, dimethyl sulfoxide or a mixture thereof.

The reaction temperature of cyanation is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of cyanation is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

The reducing agent to be used for reduction of the cyano group incompound (XXXVII) may be, for example, a metallic reducing reagent suchas aluminum lithium hydide, sodium borohydride and lithium borohydride,or diborane.

The solvent to be used for cyanation may be, for example,tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol,2-propanol, tert-butyl alcohol, ethylene glycoldimethyl ether, a mixturethereof, and the like.

The reaction temperature of reduction of the cyano group is generallyfrom −20° C. to 80° C., and a temperature above or under this range canbe employed as necessary.

The reaction time of reduction of the cyano group is generally from 30minutes to 10 hours, and a time longer or shorter than this range can beemployed as necessary.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method S

Compound (XXXVII) can be also produced by the following method.

wherein each symbol is as defined above.

In this method, the conditions of cyanation are the same as in Method Rand those of condensation are the same as in Method A.

After cyanation and condensation under the above-mentioned reactionconditions and, where necessary, removal of protecting group(s), thesynthetic intermediate in each step and the objective compound can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method T

Compound (XXV) wherein R¹ is hydrogen and R² is nitro can be produced bythe following method.

wherein each symbol is as defined above.

By this nitration, compound (XXV-b) is mainly produced.

The reagent to be used for nitration may be, for example, nitric acid,mixed acid, acetyl nitrate, dinitrogen pentaoxide or nitronium salt.

The solvent to be used for nitration may be, for example, water, aceticacid, acetic anhydride, con. sulfuric acid, chloroform, dichloromethane,carbon disulfide, dichloroethane or a mixture thereof, or the solventmay not be used.

The reaction temperature of nitration is generally from −20° C. to 80°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of nitration is generally from 30 minutes to 10 hours,and a time longer or shorter than this range can be employed asnecessary.

After nitration under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (XXV-b), compound(XXV-c) can be purified by a method known in the field of organicsynthetic chemistry, such as solvent extraction, recrystallization,chromatography, and a method using an ion exchange resin.

Further, compound (XXV-b) and compound (XXV-c) are reacted in the samemanner as in Method L to produce compound (I-8a)

wherein each symbol is as defined above.

Method U

Compound (I-8) wherein R¹ is hydrogen and R² is amino can be produced bythe following method.

wherein each symbol is as defined above.

The reducing agent to be used for reduction of the nitro group may be,for example, a metallic reducing reagent (e.g., sodium borohydride,lithium borohydride, aluminum lithium hydide and the like), reductionusing metal (e.g., iron, zinc, tin and the like), and catalyticreduction using transition metal (e.g., palladium-carbon, platinumoxide, Raney-nickel, rhodium, ruthenium and the like). When catalyticreduction is applied, ammonium formate, sodium dihydrogenphosphate,hydrazine and the like can be used as the hydrogen source.

The solvent to be used for reduction of the nitro group may be, forexample, water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran,diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene,toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixturethereof.

The reaction temperature of reduction of nitro is generally from −20° C.to 150° C., and a temperature above or under this range can be employedas necessary.

The reaction time of reduction of nitro is generally from 30 minutes to2 days, and a time longer or shorter than this range can be employed asnecessary.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-8b) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

In compound (I-8b), when R⁶ and R⁷ are not hydrogen and R³, R⁴ and R⁵are not amino, the functional group (hydroxy and the like) are protectedas necessary, and the compound is subjected to the reactions asdescribed in Method B1 to Method B8 to produce a compound wherein theamino group on the corresponding phenylene ring has been alkylatedand/or acylated.

Method V

Compound (I-8) wherein R¹ is hydrogen, R² is hydrogen, halogen (e.g.,fluorine, chlorine, bromine or iodine), hydroxy or cyano can be producedby the following method.

wherein Rg is hydrogen, halogen (e.g., fluorine, chlorine, bromine oriodine), hydroxy or cyano, and the other symbols are as defined above.

As the Sandmeyer type reaction, Sandmeyer reaction, Gattermann reaction,Schiemann reaction and the like are exemplified. The Sandmeyer typereaction comprises processes of diazotization of amine and nucleophilicsubstitution of the resulting diazonium salt using various nucleophiles.

For diazotization, an aqueous sodium nitrite solution, nitrous acid andorganic nitrite ester (e.g., isopentyl nitrite) are generally used.

The solvent to be used for diazotization may be, for example, water,hydrochloric acid, hydrobromic acid, nitric acid, dilute sulfuric acid,benzene, toluene or a mixture thereof.

The reaction temperature of diazotization is generally from −20° C. to100° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of diazotization is generally from 10 minutes to 5hours, and a time longer or shorter than this range can be employed asnecessary.

The reagent to be used for nucleophilic substitution may be, forexample, hypophosphorous acid, fluoroboric acid, hydrochloricacid—copper(I) chloride, hydrochloric acid—Gattermann copper,hydrobromic acid—copper(I) bromide, hydrobromic acid—Gattermann copper,iodine, potassium iodide, sodium iodide, trimethylsilyl iodide, water,copper(I) cyanide, sodium cyanide, potassium cyanide and the like.

The solvent to be used for nucleophilic substitution may be, forexample, water, hydrochloric acid, hydrobromic acid, nitric acid, dilutesulfuric acid, benzene, toluene, chloroform, dichloromethane,acetonitrile or a mixture thereof.

The reaction temperature of nucleophilic substitution is generally from−20° C. to 100° C., and a temperature above or under this range can beemployed as necessary.

The reaction time of nucleophilic substitution is generally from 30minutes to 5 hours, and a time longer or shorter than this range can beemployed as necessary.

After nucleophilic substitution under the above-mentioned reactionconditions and, where necessary, removal of protecting group(s),compound (I-8c) can be purified by a method known in the field oforganic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Method W

Compound (XXV) wherein R¹ is hydrogen and R² is amino can be produced bythe following method.

wherein each symbol is as defined above.

The reaction conditions of reduction of nitro are the same as in MethodU.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (XXV-d) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Further, the amino group of compound (XXV-d) is protected and reacted inthe same manner as in Method L to produce compound (I-8b).

Method X

Compound (XXV) wherein R¹ is hydrogen, R² is hydrogen, halogen (e.g.,fluorine, chlorine, bromine or iodine), hydroxy or cyano can be producedby the following method.

wherein each symbol is as defined above.

The reaction conditions of Sandmeyer type reaction are the same as inMethod V.

After Sandmeyer type reaction under the above-mentioned reactionconditions and, where necessary, removal of protecting group(s),compound (XXV-e) can be purified by a method known in the field oforganic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Further, compound (XXV-e) is reacted in the same manner as in Method Lto produce compound (I-8c).

Method Y

Compound (XXIX) wherein R¹ is hydrogen and R² is nitro can be producedby the following method.

wherein each symbol is as defined above.

The reaction conditions of nitration are the same as in Method T.

After nitration under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (XXIX-b) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Further, compound (XXIX-b) is reacted in the same manner as in Method M,Method G or Method I to produce compound (I-9a)

wherein each symbol is as defined above.

Method Z

Compound (I-9) wherein R¹ is hydrogen and R² is amino can be produced bythe following method.

wherein each symbol is as defined above.

The reaction conditions of reduction are the same as in Method U.

After reduction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), compound (I-9b) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

In compound (I-9b) , when R⁶ and R⁷ are not hydrogen and R³, R⁴ and R⁵are not amino, the functional group (hydroxy and the like) are protectedas necessary, and the compound is subjected to the reactions asdescribed in Method B1 to Method B8 to produce a compound wherein theamino group on the corresponding phenylene ring has been alkylatedand/or acylated.

Method AA

Compound (I-9) wherein R¹ is hydrogen and R² is hydrogen, halogen (e.g.,fluorine, chlorine, bromine or iodine), hydroxy or cyano can be producedby the following method.

wherein each symbol is as defined above.

The reaction conditions of Sandmeyer type reaction are the same as inMethod V.

After Sandmeyer type reaction under the above-mentioned reactionconditions and, where necessary, removal of protecting group(s),compound (I-9c) can be purified by a method known in the field oforganic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Method BB

The compound (X) can be produced by subjecting compound (XII) toMitsunobu reaction in the same manner as in Method F using hydrogenazide.

The reaction conditions (reagent, solvent, reaction temperature,reaction time) of Mitsunobu reaction are the same as in Method F.

After Mitsunobu reaction under the above-mentioned reaction conditions,the protecting group(s) is/are removed as necessary, and compound (X)can be purified by a method known in the field of organic syntheticchemistry, such as solvent extraction, recrystallization,chromatography, and a method using an ion exchange resin.

Method CC

Compound (I) wherein Y is methylene and R⁸ and R⁹ are both hydrogen canbe produced by the following method.

wherein Hal is halogen such as chlorine, bromine, iodine and the like,and the other symbols are as defined above.

The halogenizing agent to be used for the halogenation of compound (XL)may be, for example, halogen (e.g., chlorine, bromine, iodine and thelike), N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride,hypohalite tert-butyl and the like. For acceleration of the reaction, aradical initiator such as dibenzoyl peroxide, azobisisobutyronitrile andthe like can be used. In addition, the reaction may be carried out underheat or light for acceleration of the reaction.

The solvent to be used for halogenation is preferably carbontetrachloride.

The reaction temperature of halogenization is generally from 0° C. to100° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of halogenization is generally 1 to 12 hours, and atime longer or shorter than this range can be employed as necessary.

The reducing agent to be used for reduction of compound (XLI) may be,for example, those used in catalytic reduction such asdiisobutylaluminum hydride, sodium borohydride—cobalt (II) chloride,aluminum lithium hydride—aluminum chloride, lithium trimethoxyaluminumhydride, borane—methyl sulfide and transition metal (e.g.,palladium-carbon, platinum oxide, Raney-nickel, rhodium, ruthenium andthe like).

The solvent to be used for reduction may be, for example, methanol,ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane,ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide and the like.

The reaction temperature of reduction is generally from −20° C. to 80°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of reduction is generally from 30 minutes to 24 hours,and a time longer or shorter than this range can be employed asnecessary.

The compound resulting from reduction is alkylated, aralkylated,acylated or protected by a protecting group as necessary by a methodknown in the field of organic synthetic chemistry to live compound(II-c).

Further, compound (II-c) and compound (III) are condensed in the samemanner as in Method A to produce compound (I-10).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method DD

Compound (III) can be produced by the following method.

wherein Ac is acetyl, and the other symbols are as defined above.

The compound (XLII) and 1-acetylpiperazine are condensed under the samereaction conditions as in Method K.

The reagent used for hydrolysis of compound (III-a) may be, for example,hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid,sodium hydroxide, potassium hydroxide, barium hydroxide, lithiumhydroxide and the like.

The solvent to be used for hydrolysis may be, for example, water,methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, acetone,tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide,dimethyl sulfoxide or a mixture thereof.

The reaction temperature of hydrolysis is generally from −20° C. to 100°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of hydrolysis is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

The solvent to be used for condensation to directly obtain compound(III) from compound (XLII) and piperazine may be, for example, methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran,dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene,dichloromethane, dichloroethane, chloroform, toluene, xylene, hexane,dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixturethereof, or the solvent may not be used.

The reaction temperature of condensation is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method EE

Compound (III) can be also produced by the following method.

wherein each symbol is as defined above.

The reducing agent to be used for reduction of the nitro group incompound (XLIII) may be, for example, a metallic reducing reagent suchas sodium borohydride, lithium borohydride, aluminum lithium hydide andthe like, reduction with metal (e.g., iron, zinc, tin and the like), andcatalytic reduction using transition metal (e.g., palladium-carbon,platinum oxide, Raney nickel, rhodium, ruthenium and the like). Whencatalytic reduction is applied, ammonium formate, sodiumdihydrogenphosphate, hydrazine and the like can be used as the hydrogensource.

The solvent to be used for reduction of the nitro group may be, forexample, water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran,diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene,toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixturethereof.

The reaction temperature of reduction of nitro is generally from −20° C.to 80° C., and a temperature above or under this range can be employedas necessary.

The reaction time of reduction is generally 1 to 24 hours, and a timelonger or shorter than this range can be employed as necessary.

The compound (XIX) and compound (XVII-a) are condensed under the samereaction conditions as in Method A to produce compound (III).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method FF

The compound (I) wherein Y is a group of the formula

wherein each symbol is as defined above,and R⁹ is hydrogen, can beproduced by the following method.

wherein G is a hydroxyl group or lower alkoxy, and the other symbols areas defined above.

The organic solvent to be used for addition reaction of compound (XLIV)may be, for example, tetrahydrofuran, diethyl ether, ethyleneglycoldimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene,toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethaneand the like.

The reaction temperature of addition is generally from −20° C. to 100°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of addition is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

The reducing agent to be used for reduction of compound (XLV) may be,for example, sodium borohydride, lithium borohydride, aluminum lithiumhydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride,lithium tri-tert-butoxyaluminum hydride, diborane and the like.

The organic solvent to be used for reduction may be, for example,methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether,ethylene glycol dimethyl ether, acetone and methyl ethyl ketone.

The reaction temperature of reduction is generally from −100° C. to 80°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of reduction is generally from 30 minutes to 10 hours,and a time longer or shorter than this range can be employed asnecessary.

The organic solvent to be used for Ritter reaction of compound (XLVI)may be, for example, hydrogen cyanide, acetonitrile, benzonitrile andthe like.

The organic solvent to be used for Ritter reaction may be, for example,acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethylether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,dioxane, methylene chloride, chloroform, dichloroethane and the like.

The acid catalyst to be used for Ritter reaction may be, for example,strong acid such as sulfuric acid, trifluoroacetic acid and the like.

The reaction temperature of Ritter reaction is generally from −20° C. to80° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of Ritter reaction is generally from 30 minutes to 24hours, and a time longer or shorter than this range can be employed asnecessary.

The compound obtained by Ritter reaction is hydrolyzed, alkylated,aralkylated, acylated or protected by a protecting group as necessary bya method known in the field of organic synthetic chemistry to producecompound (XLVII).

The compound (XLVII) and compound (III) are condensed under the samereaction conditions as in Method A to produce compound (I-11).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method GG

The compound (I) wherein Y is a group of the formula

wherein each symbol is as defined above, and R⁹ is hydrogen, can beproduced by the following method.

wherein each symbol is as defined above.

The addition reaction of compound (XLV) and Ritter reaction of compound(XLVIII) can be carried out under the same reaction conditions as inMethod FF.

The compound (XLIX) and compound (III) are condensed under the samereaction conditions as in Method A.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method HH

Compound (XXIX) and compound (XXX) can be also produced by the followingmethod.

wherein each symbol is as defined above.

The azidating agent to be used for azidation of compound (L) isexemplified by metal azide (e.g., sodium azide, lithium azide and thelike) and the like.

The reaction temperature of azidation is generally from 0° C. to 100°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of azidation is generally 1 to 24 hours, and a timelonger or shorter than this range can be employed as necessary.

The reducing agent to be used for reduction of compound (LI) may be, forexample, a metallic reducing reagent such as sodium borohydride, lithiumborohydride, aluminum lithium hydride and the like, triphenylphosphine,and catalytic reduction using transition metal (Lindlar catalyst(palladium, calcium carbonate), palladium-carbon, Raney nickel, platinumoxide, rhodium, ruthenium and the like). For the selective reduction ofthe azide group alone of compound (LI), catalytic reduction usingtriphenylphosphine or transition metal is particularly effective.

The organic solvent to be used for reduction may be, for example,methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether,dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene,dimethylformamide, dimethyl sulfoxide and the like.

The reaction temperature of reduction is generally from −20° C. to 80°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of reduction is generally 1 to 24 hours, and a timelonger or shorter than this range can be employed as necessary.

The compound obtained by reduction is alkylated, aralkylated, acylatedor protected by a protecting group as necessary by a method known in thefield of organic synthetic chemistry to produce compound (XXIX).

After reaction under the above-mentioned reaction conditions and, wherenecessary, removal of protecting group(s), the synthetic intermediate ineach step and the objective compound can be purified by a method knownin the field of organic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Method II

Compound (I) wherein Y is methylene and R⁸ and R⁹ are the same ordifferent and each is lower alkyl can be produced by the followingmethod.

wherein R^(9a) is lower alkyl, and the other symbols are as definedabove.

The base to be used for condensation of compound (LII) may be, forexample, sodium methoxide, sodium ethoxide, sodium hydride, potassiumhydride, lithium diisopropylamide, lithium hexamethyldisilazane,diisopropylethylamine, 1,8-diazabicyclo[4.3.0]undeca-5-ene, sodium amideand the like.

The organic solvent to be used for condensation may be, for example,methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether,ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide,benzene, toluene, xylene, dioxane, methylene chloride, chloroform,dichloroethane, acetonitrile and the like.

The reaction temperature of condensation is generally from −20° C. to150° C., and a temperature above or under this range can be employed asnecessary.

The reaction time of condensation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

The base to be used for hydrolysis of compound (LIII) may be, forexample, acid such as hydrochloric acid, sulfuric acid, formic acid,acetic acid and the like, or alkali such as sodium hydroxide, potassiumhydroxide and the like.

The solvent to be used for hydrolysis may be, for example, water,methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethyleneglycol, diethylene glycol, a mixture thereof, and the like.

The reaction temperature of hydrolysis is generally from −20° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of hydrolysis is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

After halogenation of compound (LIV), the compound is subjected toazidation to produce compound (LIX). The halogenation of compound (LIV)can be performed under the same reaction conditions as in Method CC. Theobtained halogenated compound is subjected to azidation under the samereaction conditions as in Method HH.

The compound (LV) is reduced under the same reaction conditions as inMethod HH.

The base to be used for curtius rearrangement of compound (LVI) may be,for example, Hünig base such as triethylamine, diisopropylethylamine andthe like. When the substrate of this reaction, carboxylic acid, is asalt, a base is not necessary.

The activator to be used for Curtius rearrangement is exemplified bymethyl chlorocarbonate, ethyl chlorocarbonate, isopropylchlorocarbonate, isobutyl chlorocarbonate, phenyl chlorocarbonate andthe like.

The azidating agent to be used for Curtius rearrangement is exemplifiedby sodium azide, diphenylphosphoryl azide (when this reagent is used,base or activator is not necessary) and the like.

The solvent to be used for Curtius rearrangement may be, for example,aprotic solvent in the former half of the reaction, such astetrahydrofuran, acetone, diethyl ether, ethylene glycol dimethyl ether,dimethylformamide, dimethyl sulfoxide, dioxane, methylene chloride,chloroform, dichloroethane, acetonitrile and the like, and in the latterhalf of the reaction, for example, methanol, ethanol, tert-butylalcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether,dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile orbenzyl alcohol is used.

The reaction temperature of Curtius rearrangement is generally from −20°C. to 150° C., and a temperature above or under this range can beemployed as necessary.

The reaction time of Curtius rearrangement is generally from 30 minutesto 10 hours, and a time longer or shorter than this range can beemployed as necessary.

The carbamic acid compound obtained by Curtius rearrangement is treatedwith benzyl alcohol and subjected to catalytic reduction to producecompound (LVII). When carbamic acid compound is treated with an alcoholsolution of acid (e.g., hydrochloric acid, sulfuric acid and the like)or alkali (e.g., sodium hydroxide, potassium hydroxide and the like), ortrimethylsilyl iodide, compound (LVII) can be produced.

The compound (LVII) and compound (XXI) are condensed under the samereaction conditions as in Method J.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method JJ

Compound (XVIII) can be produced by the following method.

wherein each symbol is as defined above.

The compound (XX) and compound (XXIIa) are condensed under the samereaction conditions as in Method J.

The compound (XX) and compound (XXIIc) are condensed under the samereaction conditions as in Method J. The compound (XXb) is reduced underthe same reaction conditions as in Method J.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method KK

Compound (I) wherein m=n=0, R¹² and R¹³ in combination form ethylene andR⁸ and R⁹ are both hydrogen can be produced by the following method.

wherein each symbol is as defined above.

The compound (LXI) is halomethylated under the same reaction conditionsas in Method N.

The compound (LXII) and compound (III) are condensed under the samereaction conditions as in Method A.

The compound (LXIII) is subjected to Curtius rearrangement under thesame reaction conditions as in Method II. The carbamic acid compoundobtained by Curtius rearrangement is reacted with a Grignard reagent toproduce compound (I-13) wherein R⁶ or R⁷ is acylated. The amine compoundobtained by Curtius rearrangement is alkylated, aralkylated or acylatedby a method known in the field of organic synthetic chemistry to producecompound (I-13).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method LL

Compound (I) wherein m=n=0, R¹² and R¹³ in combination form ethylene andR⁹ is hydrogen can be produced by the following method.

wherein each symbol is as defined above.

The compound (LXIV) is subjected to Curtius rearrangement under the samereaction conditions as in Method KK.

The Friedel-Crafts reaction of compound (LXV) and reduction of compound(LXVI) can be carried our under the same reaction conditions as inMethod M. The hydroxyl group of compound (LXVII) is converted to aleaving group Lv by a method known in the field of organic syntheticchemistry to give compound (LXVIII), which is then condensed withcompound (III) in the same manner as in Method A to produce compound(I-14).

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

Method MM

Compound (XXIV) wherein Lv₁ is chlorine or bromine can be produced bythe following method.

wherein each symbol is as defined above.

The compound (XIX) is subjected to Sandmeyer type reaction under thesame reaction conditions as in Method V.

After Sandmeyer type reaction under the above-mentioned reactionconditions and, where necessary, removal of protecting group(s),compound (XXIV) can be purified by a method known in the field oforganic synthetic chemistry, such as solvent extraction,recrystallization, chromatography, and a method using an ion exchangeresin.

Method NN

Compound (XXIV) wherein Lv₁ is chlorine can be produced by the followingmethod.

wherein each symbol is as defined above.

This method is particularly effective for converting the hydroxyl groupof hetero ring derivative, such as 2-hydroxypyrimidine,2-hydroxypyridine and the like, to chloride.

The reagent to be used for chlorination of compound (LXIX) may be, forexample, phosphorous oxychloride.

The solvent to be used for chlorination may be, for example,dichloromethane, dichloroethane, chloroform, carbon tetrachloride or amixture thereof, or the reaction proceeds without solvent.

The reaction temperature of chlorination is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of chlorination is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

After chlorination under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), compound (XXIV) can bepurified by a method known in the field of organic synthetic chemistry,such as solvent extraction, recrystallization, chromatography, and amethod using an ion exchange resin.

Method OO

Compound (XXVII) wherein m=n=0 at Y can be produced by the followingmethod.

wherein each symbol is as defined above.

The reagent to be used for halogenation of compound (LXX) may be, forexample, N-bromosuccimide and N-chlorosuccimide.

For the halogenation, a radical initiator such as2,2′-azobisisobutyronitrile (AIBN), benzoyl peroxide and the like can beused as necessary.

The solvent to be used for halogenation may be, for example, carbontetrachloride, chloroform, dichloromethane or benzene.

The reaction temperature of halogenation is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of halogenation is generally from 30 minutes to 2days, and a time longer or shorter than this range can be employed asnecessary.

The reagent to be used for ammonolysis of compound (LXXI) may be, forexample, liquid ammonia.

The solvent to be used for ammonolysis may be, for example, water,methanol, ethanol, 1-propanol, tetrahydrofuran, dioxane or a mixturethereof.

The reaction temperature of ammonolysis is generally from 0° C. to 150°C., and a temperature above or under this range can be employed asnecessary.

The reaction time of ammonolysis is generally from 30 minutes to 2 days,and a time longer or shorter than this range can be employed asnecessary.

The compound (LXXII) can be converted to compound (XXVII) according toMethods B1 to B8.

After each reaction under the above-mentioned reaction conditions and,where necessary, removal of protecting group(s), the syntheticintermediate in each step and the objective compound can be purified bya method known in the field of organic synthetic chemistry, such assolvent extraction, recrystallization, chromatography, and a methodusing an ion exchange resin.

The compound (I) of the present invention can be treated with an acid(e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaricacid, benzoic acid, citric acid, succinic acid, tartaric acid, malicacid, mandelic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like), asnecessary, in a suitable solvent (e.g., water, methanol, ethanol,diethyl ether, tetrahydrofuran, dioxane and the like) to convert to apharmaceutically acceptable salt. The compound (I) of the presentinvention can be converted to a quaternary ammonium salt by treatingwith lower alkyl halide (e.g., methyl iodide, methyl bromide, ethyliodide, ethyl bromide and the like) in the presence of a base. When theobtained crystals of the compound of the present invention areanhydride, the compound of the present invention is treated with water,a water-containing solvent or a different solvent to give a hydrate(e.g., monohydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate,3/2 hydrate, 3/4 hydrate and the like) or solvate.

The compound of the present invention thus obtained can be isolated andpurified by a conventional method such as recrystallization, columnchromatography and the like. When the resulting product is a racemate,for example, a desired optically active compound can be resolved byfractional recrystallization of a salt with an optically active acid orby passing the racemate through a column packed with an optically activecarrier. Individual diastereomers can be separated by fractionalcrystallization, chromatography and the like. These can be also obtainedby using an optically active starting compound.

The compound of the present invention has a TNF-α production inhibitoryeffect and/or IL-10 production promoting effect, and is useful for theprophylaxis and treatment of various diseases caused by abnormal TNF-αproduction, diseases treatable with IL-10, such as chronic inflammatorydisease, acute inflammatory disease, inflammatory disease due toinfection, autoimmune diseases, allergic diseases, and other TNF-αmediated diseases.

The chronic inflammatory diseases include osteoarthritis, psoriaticarthritis, inflammatory dermal disease (psoriasis, eczematoiddermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullouspemphigoid, epidermolysis bullosa, urticaria, vascular edema, angiitis,erythema, dermal eosinophilia, acne, alopecia areata, eosinophilicfasciitis, atherosclerosis and the like), inflammatory bowel disease(ulcerative colitis, Crohn's disease and the like) and the like.

The acute inflammatory diseases include contact dermatitis, adultrespiratory distress syndrome (ARDS), sepsis (inclusive of organdisorders etc. caused by sepsis), septic shock, and the like.

The inflammatory diseases due to infection include endotoxin shock,acquired immunodeficiency syndrome (AIDS), meningitis, cachexia, viralhepatitis, fulminant hepatitis, other inflammatory responses due toinfection with bacteria, virus, mycoplasma and the like (inclusive offever, pain, organ disorders caused by influenzal or non-influenzal coldand the like) and the like.

The autoimmune diseases include rheumatoid arthritis, ankylosingspondylitis, systemic lupus erythematosus, glomerular nephritis(nephrotic syndrome (idiopathic nephrotic syndrome, minimal-changenephropathy and the like) and the like), multiple sclerosis,polychondritis, scleroderma, dermatomyositis, wegener's granulomatosis,active chronic hepatitis I, primary biliary cirrhosis, myastheniagravis, idiopathic sprue, Graves' disease, sarcoidosis, Reiter'ssyndrome, juvenile diabetes (type I diabetes mellitus), autoimmuneophthalmic disease (endocrine ophthalmopathy, uveitis, keratitis(keratoconjunctivitis sicca, vernal keratoconjunctivitis and the like)and the like), Behqet's disease, autoimmune hemopathy (hemolytic anemia,aplastic anemia, idiopathic thrombocytopenia and the like), variousmalignant tumors (adenocarcinoma and the like), matastatic carcinoma andthe like.

The allergic diseases include atopic dermatitis, asthmatic diseases(bronchial asthma, infantile asthma, allergic asthma, intrinsic asthma,extrinsic asthma, dust asthma, late-onset asthma, bronchialhypersensitivity, bronchitis and the like), allergic rhinitis, allergicconjunctivitis and the like.

Other TNF-α mediated diseases include resistant responses in organ ortissue transplantation (e.g., allograft or xenograft of heart, kidney,liver, lung, bone marrow, cornea, pancreas, pancreatic cell, smallintestine, duodenum, limbs, muscle, nerve, fatty marrow, skin and thelike) in mammals such as human, dog, cat, cow, horse, swine, monkey,mice and the like, i.e., rejection and graft versus host disease (GvHD),osteoporosis, cancer cachexia, thermal burn, trauma, scald, inflammatoryresponse (inclusive of shock)and the like against plant and animalcomponents (inclusive of snake venom and the like) and administration ofdrug and the like, myocardial infarction, chronic heart failure,congestive heart failure, ischemia-reperfusion injury, Kawasaki disease,pneumonia, malaria, meningitis, peritonitis, fibroid lung anddisseminated intravascular coagulation (DIC). In addition to these, theinventive compound is useful for the prophylaxis and treatment ofhepatopathy.

The compound of the present invention is characteristically void ofeffect on the central nervous system, because it has no or extremelyweak affinity for the receptors distributed in the central nervoussystem. Moreover, the compound of the present invention having a TNF-αproduction inhibitory effect and an IL-10 production promoting effect isexpected to show superior prophylactic and therapeutic effects on theabove-mentioned diseases, particularly chronic diseases such asrheumatoid arthritis, chronic inflammatory diseases and the like, by thesynergistic action of these two effects. In the present invention, acompound having these two effects is preferable.

When the compound (I) of the present invention is used as a TNF-αproduction inhibitor and/or an IL-10 production promoter, it is preparedinto a typical pharmaceutical preparation. For example, the compound ofthe present invention (I) is prepared into a dosage form suitable fororal or parenteral administration upon admixing with a pharmaceuticallyacceptable carrier (excipient, binder, disintegrant, corrigent, flavor,emulsifier, diluent, solubilizer and the like) to give a pharmaceuticalcomposition or preparation, such as tablet, pill, powder, granule,capsule, troche, syrup, liquid, emulsion, suspension, injection (liquid,suspension and the like), suppository, inhalent, transdermal absorber,eye drop, nose drop, eye ointment and the like.

When a solid preparation is produced, an additive is used, such assucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran,starches, agar, arginates, chitins, chitosans, pectins, tragacanth,acacia, gelatins, collagens, casein, albumin, calcium phosphate,sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerol,polyethylene glycol, sodium hydrogencarbonate, magnesium stearate, talcand the like. The tablets can be made into those having typical tabletfilm, as necessary, such as sugar-coated tablet, enteric coated tablet,film coating tablet, or two-layer tablet, or multi-laye tablet.

When a semi-solid preparation is produced, plant and animal fats andoils (olive oil, corn oil, castor oil and the like), mineral oils(petrolatum, white petrolatum, solid paraffin and the like), wax (jojobaoil, carnauba wax, bee wax and the like), partially synthesized orcompletely synthesized glycerol fatty acid ester (lauric acid, myristicacid, palmitic acid and the like), and the like are used. Commerciallyavailable products of these are, for example, Witepsol (manufactured byDynamitnovel Ltd.), pharmasol (manufactured by Japan Oil & Fat Co. Ltd.)and the like.

When a liquid preparation is produced, an additive is used, such assodium chloride, glucose, sorbitol, glycerol, olive oil, propyleneglycol, ethyl alcohol and the like. In particular, when an injection isprepared, sterile aqueous solution, such as physiological saline,isotonic liquid and oily liquid (e.g., sesami oil and soybean oi) areused. Where necessary, a suitable suspending agent, such as sodiumcarboxymethylcellulose, nonionic surfactant and solubilizer (e.g.,benzyl benzoate, benzyl alcohol and the like) may be used concurrently.Further, when an eye drop or nasal drop is given, an aqueous liquid oraqueous solution is used, particularly, sterile aqueous solution forinjection. The liquid for eye drop or nasal drop may contain variousadditives as appropriate, such as buffer (borate buffer, acetate buffer,carbonate buffer and the like are preferable for reducing irritation),isotonicity agent, solubilizer, preservative, viscous agent, chelatingagent, pH adjusting agent (pH is preferably adjusted generally to about6-8.5) and aromatic.

The amount of the active ingredient in these preparations is 0.1-100 wt%, suitably 1-50 wt %, of the preparation. The dose varies depending onthe condition, body weight, age and the like of patients. In the case oforal administration, it is generally about 0.01-50 mg per day for anadult, which is administered once or in several doses.

EXAMPLES

The present invention is explained in detail in the following by way ofExamples which do not limit the present invention. Of the symbols usedin the chemical structures, Ac means acetyl, Me means methyl and Etmeans ethyl.

Example 1 Synthesis ofN-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 4-Acetamidomethylbenzoic Acid

To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in ethyl acetate(100 ml) was added an aqueous sodium hydroxide (12 g) solution (100 ml)and acetic anhydride (14 ml) was further added at 5-7° C. This reactionmixture was stirred at room temperature for 1 hr and made acidic with10% hydrochloric acid and extracted with ethyl acetate:ethanol (10:1)(100 ml×5). The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated to give apale-yellow solid (27.2 g). The obtained solid was crystallized fromethyl acetate:ethanol (1:1,500 ml) to give the objective compound (16.7g) as white crystals, m.p. 200-202° C.

¹H-NMR(DMSO-d₆) δ: 1.89(3H, s), 4.32(2H, d, J=5.9 Hz), 7.36(2H, d, J=7.9Hz), 7.89(2H, d, J=8.6 Hz), 8.41(1H, m), 12.84(1H, br.s); IR(KBr): 3298,1691, 1646, 1539 cm⁻¹; MS(EI): 193(M⁺); Elemental analysis: Calculated:C; 62.17, H; 5.74, N; 7.25; Found: C; 62.01, H; 5.71, N; 7.21.

(2) Methyl 4-Acetamidomethylbenzoate

4-Acetamidomethylbenzoic acid(4.0 g) was dissolved in 0.5% hydrochloricacid—methanol solution (100 ml). The mixture was stirred at 40° C. for3.5 hr, and poured into ice water (300 ml) and extracted with ethylacetate (100 ml×4). The extract was washed with saturated sodiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated to give a pale-yellow solid(4.3 g). The obtained solid was crystallized from ethyl acetate (50 ml)to give the title compound (3.2 g) as pale-yellow white crystals,m.p.=110-111° C.

¹H-NMR(DMSO-d₆) δ: 1.90(3H, s), 3.84(3H, s), 4.33(2H, d, J=5.9 Hz),7.39(2H, d, J=8.6 Hz), 7.92(2H, d, J=7.9 Hz), 8.43(1H, m); IR(KBr):3277, 1727, 1643, 1556 cm⁻¹; MS(EI): 207(M⁺); Elemental analysis:Calculated: C; 63.76, H; 6.32, N; 6.76; Found: C; 63.76, H; 6.38, N;6.76.

(3) N-(4-Hydroxymethylphenylmethyl)acetamide

To a suspension of aluminum lithium hydride (570 mg) in tetrahydrofuran(80 ml) was added a solution of methyl 4-acetamidomethylbenzoate (3.1 g)in tetrahydrofuran (20 ml) under ice-cooling. The mixture was stirred atroom temperature for 1.5 hr and a saturated aqueous sodium sulfatesolution (7 ml) was added at 100° C. The mixture was stirred at roomtemperature for 1 hr. The sediment was filtrated and the solvent wasevaporated to give the title substance (2.8 g) as a white solid.

¹H-NMR(DMSO-d₆) δ: 1.86(3H, s), 4.22(2H, d, J=5.9 Hz), 4.46(2H, s),5.13(1H, br.s), 7.19(2H, d, J=7.9 Hz), 7.25(2H, d, J=8.6 Hz), 8.30(1H,m); MS(EI): 179(M⁺).

(4) N-(4-Chloromethylphenylmethyl)acetamide

To a solution of N-(4-hydroxymethylphenylmethyl)acetamide (1.5 g) inchloroform (50 ml) was added thionyl chloride (0.73 ml) and the mixturewas refluxed under heating for 1 hr. The solvent was evaporated and theobtained residue was crystallized from ethyl acetate to give the titlecompound (1.8 g) as pale-yellow crystals.

m.p.=116-118° C.; ¹H-NMR(CDCl₃) δ: 2.01(3H, s), 4.40(2H, d, J=5.9 Hz),4.56(2H, s), 6.20(1H, br.s), 7.26(2H, d, J=8.6 Hz), 7.34(2H, d, J=7.9Hz); MS(EI): 197(M⁺).

(5) N-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.65 g),1-phenylpiperazine (1.3 ml) and potassium carbonate (1.2 g) indimethylformamide (50 ml) was stirred at 60° C. for 1 hr. The reactionmixture was poured into water (200 ml) and extracted with ethyl acetate(100 ml×3). The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated to give a brownsolid (4.4 g). The obtained solid was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=10:1) to give apale-brown solid (3.45 g). The obtained solid was crystallized fromethyl acetate and the crystals were recrystallized from a mixture ofethyl acetate, ethanol and hexane to give the title compound (1.4 g) aswhite crystals, m.p.=135-136° C.

¹H-NMR(DMSO-d₆) δ: 1.87(3H, s), 2.50(4H, m), 3.11(4H, m), 3.49(2H, s),4.23(2H, d, J=5.9 Hz), 6.76(1H, t, J=7.3 Hz), 6.90(2H, d, J=7.9 Hz),7.15-7.29(6H, m), 8.30(1H, t, J=5.9 Hz); IR(KBr): 3318, 2813, 1645, 1538cm⁻¹; MS(EI): 323(M⁺); Elemental analysis: Calculated: C; 74.27, H;7.79, N; 12.99; Found: C; 74.01, H; 7.88, N; 12.77.

Example 2 Synthesis of4-((4-(Aminomethyl)phenyl)methyl)-1-phenylpiperazine

N-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide (2.6 g) wasdissolved in 10% hydrochloric acid (50 ml) and the mixture was refluxedunder heating for 6 hr. To the mixture was added 10% aqueous sodiumhydroxide solution to make it alkaline and the mixture was extractedwith ethyl acetate (100 ml×3). The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated and the obtained residue was crystallized from water-ethanolto give the title compound (1.34 g) as white crystals, m.p.=68-70° C.

¹H-NMR(DMSO-d₆) δ: 2.40-2.50(4H, m), 3.05-3.15(4H, m), 3.10-3.45(2H,br.s), 3.48(2H, s), 3.69(2H, s), 6.76(1H, t, J=7.3 Hz), 6.90(2H, d,J=7.9 Hz), 7.15-7.30(6H, m); IR(KBr): 3359, 2805, 1602, 1506 cm⁻¹;MS(EI): 281(M⁺); Elemental analysis: Calculated: C; 76.83, H; 8.24, N;14.93; Found: C; 76.60, H; 8.21, N; 14.59.

Example 3 Synthesis ofN-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)formamide

A mixture of acetic anhydride (0.36 ml) and formic acid (0.15 ml) wasstirred at 50-60° C. for 2 hr, and to the obtained acetic acid andformic acid anhydride was added a solution of4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.5 g) inmethylene chloride (10 ml) under ice-cooling. This reaction mixture wasstirred at 5-10° C. for 2.5 hr and left standing at room temperature for14 hr. To this reaction mixture were added ethanol (20 ml) and ethylacetate (150 ml) and the mixture was washed with saturated sodiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated to give a brown solid (0.56g). The obtained solid was purified by silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give a pale-brown solid(0.55 g). The obtained solid was crystallized from ethyl acetate-hexane(2:1) to give the title compound (0.41 g) as pale-yellow white crystals,m.p.=108-109° C.

¹H-NMR(DMSO-d₆) δ: 2.45-2.53(4H, m), 3.05-3.15(4H, m), 3.49(2H, s),4.29(2H, d, J=5.9 Hz), 6.76(1H, t, J=7.3 Hz), 6.90(2H, d, J=8.6 Hz),7.15-7.30(6H, m), 8.13(1H, d, J=1.3 Hz), 8.47(1H, m); IR(KBr): 3315,2846, 2821, 1658, 1522 cm⁻¹; MS(EI): 309(M⁺) Elemental analysis:Calculated: C; 73.76, H; 7.49, N; 13.58; Found: C; 73.36, H; 7.53, N;13.47.

Example 4 Synthesis ofN-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)propionamide

A solution of 4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.62g), propionyl chloride (0.23 ml) and triethylamine (0.37 ml) inmethylene chloride (20 ml) was stirred at room temperature for 4 hr. Tothis reaction mixture was added chloroform (100 ml), and the mixture waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a pale-brown solid (0.9 g). The obtainedsolid was crystallized from ethyl acetate (50 ml) to give the titlecompound (0.5 g) as pale-yellow white crystals, m.p.=140-141° C.

¹H-NMR(DMSO-d₆) δ: 1.03(3H, t, J=7.9 Hz), 2.14(2H, q, J=7.9 Hz),2.45-2.55(4H, m), 3.05-3.15(4H, m), 3.49(2H, s), 4.24(2H, d, J=5.9 Hz),6.76(1H, t, J=7.3 Hz), 6.90(2H, d, J=7.9 Hz), 7.15-7.30(6H, m), 8.24(2H,t, J=5.9 Hz); IR(KBr): 3318, 2940, 2819, 1645, 1535 cm⁻¹; MS(EI):337(M⁺); Elemental analysis: Calculated: C; 74.74, H; 8.06, N; 12.45;Found: C; 74.66, H; 8.11, N; 12.16.

Example 5 Synthesis ofN-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine,the title compound was obtained as white crystals, m.p.=164-166° C.

¹H-NMR(DMSO-d₆) δ: 1.87(3H, s), 2.45-2.55(4H, m), 3.00-3.10(4H, m),3.49(2H, s), 4.23(2H, d, J=5.9 Hz), 6.89-6.95(2H, m), 6.95-7.06(2H, m),7.19-7.39(4H, m), 8.30(1H, t, J=5.9 Hz); IR(KBr): 3317, 2920, 2832,1643, 1513 cm⁻¹; MS(EI): 341(M⁺) Elemental analysis: Calculated: C;70.36, H; 7.09, N; 12.31; Found: C; 70.08, H; 7.06, N; 12.13.

Example 6 Synthesis ofN-(4-((4-(2-Chlorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide·Dihydrochloride

By similar reaction using (2-chlorophenyl)piperazine instead ofphenylpiperazine to that in Example 1(5) and treatment with 4Mhydrochloric acid—dioxane in ethanol, the title compound was obtained aspale-brown crystals.

m.p.=235-238° C. (decomposition).

¹H-NMR(DMSO-d₆) δ: 1.89(3H, s), 3.10-3.40(8H, m), 4.28(2H, d, J=5.9 Hz),4.37(2H, m), 7.05-7.20(1H, m), 7.30-7.35(3H, m), 7.44(1H, dd, J=1.3, 7.9Hz), 7.63(2H, d, J=7.9 Hz), 8.45(1H, t, J=5.9 Hz), 11.43(1H, br.s);IR(KBr): 3282, 2591, 1664, 1543 cm⁻¹; MS(EI): 357(M⁺); Elementalanalysis: Calculated: C; 60.76, H; 6.23, N; 10.63; Found: C; 60.49, H;6.34, N; 10.63.

Example 7 Synthesis ofN-(4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide·Hydrochloride

By similar reaction using (2,3-dimethylphenyl)piperazine hydrochlorideinstead of phenylpiperazine to that in Example 1(5) and treatment with4M hydrochloric acid-dioxane in ethanol, the title compound was obtainedas white crystals.

m.p.=253-255° C. (decomposition); ¹H-NMR(DMSO-d₆) δ: 1.89(3H, s),2.15(3H, s), 2.21(3H, s), 3.00-3.35(8H, m), 4.28(2H, d, J=5.9 Hz),4.35(2H, s), 6.88(1H, d, J=7.9 Hz), 6.92(1H, d, J=7.3 Hz), 7.06(1H, dd,J=7.3, 7.9 Hz), 7.33(2H, d, J=8.6 Hz), 7.63(2H, d, J=8.6 Hz), 8.45(1H,m), 11.33(1H, br.s); IR(KBr): 3253, 2465, 1649, 1556 cm⁻¹; MS(EI):351(M⁺); Elemental analysis: Calculated: C; 68.11, H; 7.79, N; 10.83;Found: C; 67.74, H; 7.94, N; 10.67.

Example 8 Synthesis ofN-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide·Dihydrochloride

In Example 1(5), (2-methoxyphenyl)piperazine was used for reactioninstead of phenylpiperazine, which was followed by treatment withhydrochloric acid-ether and recrystallization from methanol-ethylacetate to give the title compound as white crystals.

m.p.=221-223° C.; ¹H-NMR(DMSO-d₆) δ: 1.89(3H, s), 3.06-3.27(4H, m),3.31-3.35(2H, m), 3.44-3.57(2H, m), 3.78(3H, s), 4.28(2H, d, J=5.9 Hz),4.34(2H, br.s), 6.86-7.05(4H, m), 7.33(2H, d, J=8.4 Hz), 7.61(2H, d,J=8.5 Hz), 8.45(1H, t, J=5.9 Hz), 11.33(1H, br.s); IR(KBr): 3263, 2487,1666, 1535 cm⁻¹; MS(EI): 353(M⁺); Elemental analysis: Calculated: C;58.88, H; 7.29, N; 9.81; Found: C; 58.45, H; 6.91, N; 9.75.

Example 9 Synthesis ofN-(4-((4-(3-Methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(3-methylphenyl)piperazine instead of phenylpiperazine, the titlecompound was obtained as pale-yellow crystals, m.p.=80-81° C.

¹H-NMR(CDCl₃) δ: 2.02(3H, s), 2.31(3H, s), 2.58(4H, dt, J=5.3, 4.7 Hz),3.18(4H, dd, J=5.3, 4.7 Hz), 3.55(2H, s), 4.42(2H, d, J=5.3 Hz),5.72(1H, br.s), 6.67(1H, d, J=7.3 Hz), 6.72(1H, d, J=7.3 Hz), 6.74(1H,s), 7.13(1H, t, J=7.3 Hz), 7.24(2H, d, J=7.9 Hz), 7.33(2H, d, J=7.9 Hz);IR(KBr): 3317, 2815, 1633, 1537 cm⁻¹; MS(EI): 337(M⁺); Elementalanalysis: Calculated: C; 74.74, H; 8.06, N; 12.54; Found: C; 74.60, H;8.04, N; 12.47.

Example 10 Synthesis ofN-(4-((4-(3-Methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 3/4 Hydrate

In Example 1(5), (3-methoxyphenyl)piperazine was used for reactioninstead of phenylpiperazine, which was followed by treatment withhydrochloric acid—ether and recrystallization from methanolethyl acetateto give the title compound as white crystals, m.p.=201.5-202.5° C.

¹H-NMR(DMSO-d₆) δ: 1.89(3H, s), 3.07-3.29(4H, m), 3.33-3.39(2H, m),3.72(3H, s), 3.77-3.81(2H, m), 4.28(2H, d, J=5.9 Hz), 4.34(2H, d, J=3.3Hz), 6.45(1H, ddd, J=8.6, 7.9, 2.0 Hz), 6.49(1H, s), 6.52(1H, ddd,J=8.6, 7.9, 2.0 Hz), 7.14(1H, ddd, J=8.6, 7.9 Hz), 7.33(2H, d, J=7.9Hz), 7.70(2H, d, J=7.9 Hz), 8.44(1H, t, J=5.9 Hz), 11.33(1H, br.s);IR(KBr): 3280, 2464, 1643, 1556 cm⁻¹ MS(EI): 353(M⁺); Elementalanalysis: Calculated: C; 62.52, H; 7.37, N; 10.42; Found: C; 62.64, H;7.34, N; 10.44.

Example 11 Synthesis ofN-(4-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(4-chlorophenyl)piperazine instead of phenylpiperazine, the titlecompound was obtained as pale-yellow crystals, m.p.=180.5-182° C.

¹H-NMR(CDCl₃) δ: 2.02(3H, s), 2.58(4H, dd, J=5.3, 4.6 Hz), 3.15(4H, dd,J=5.3, 4.6 Hz), 3.54(2H, s), 4.42(2H, d, J=5.9 Hz), 5.74(1H, br.s),6.82(2H, ddd, J=9.2, 3.3, 2.0 Hz), 7.19(2H, ddd, J=9.2, 3.3, 2.0 Hz),7.24(2H, d, J=7.9 Hz), 7.32(2H, d, J=7.9 Hz); IR(KBr): 3315, 2890, 1645,1542 cm⁻¹; MS(EI): 357(M⁺); Elemental analysis: Calculated: C; 67.12, H;6.76, N; 11.45; Found: C; 67.08, H; 6.73, N; 11.75.

Example 12 Synthesis ofN-(4-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/4 Hydrate

In Example 1(5), (2-fluorophenyl)piperazine was used for reactioninstead of phenylpiperazine, which was followed by treatment withhydrochloric acid—ether and recrystallization from a mixture ofethanol-ethyl acetate-hexane to give the title compound as pale-browncrystals, m.p.=250-252° C. (decomposition).

¹H-NMR(DMSO-d₆) δ: 1.89(3H, s), 3.15-3.60(8H, m), 4.28(2H, d, J=5.9 Hz),4.35(2H, br.s), 7.15(4H, m), 7.33(2H, d, J=7.9 Hz), 7.62(2H, d, J=7.9Hz), 8.46(1H, t, J=5.9 Hz), 11.43(1H, br.s); IR(KBr): 3265, 2679, 1664,1504 cm⁻¹; MS(EI): 341(M⁺); Elemental analysis: Calculated: C; 62.82, H;6.72, N; 10.99; Found: C; 62.60, H; 6.56, N; 11.00.

Example 13 Synthesis ofN-(4-((4-(4-Methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(4-methoxyphenyl)piperazine instead of phenylpiperazine, the titlecompound was obtained as white crystals, m.p.=137-138° C.

¹H-NMR(CDCl₃) δ: 1.87(3H, s), 2.50(4H, m), 2.99(4H, m), 3.48(2H, s),3.67(3H, s), 4.23(2H, d, J=5.9 Hz), 6.79(2H, d, J=9.2 Hz), 6.86(2H, d,J=9.2 Hz), 7.21. (2H, d, J=8.6 Hz), 7.27(2H, d, J=7.9 Hz), 8.30(1H, t,J=5.6 Hz); IR(KBr): 3325, 1649, 1514 cm⁻¹; MS(EI): 353(M⁺); Elementalanalysis: Calculated: C; 71.36, H; 7.70, N; 11.89; Found: C; 71.19, H;7.70, N; 11.77.

Example 14 Synthesis ofN-(2-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) N-(2-(4-Chloromethylphenyl)ethyl)acetamide

To a solution of N-(2-phenylethyl)acetamide (5.0 g) in dichloromethane(31 ml) was added titanium tetrachloride (17 ml) at 0-5° C. over 30 min.Thereto was added dichloromethyl methyl ether (8.4 ml) at 0-5° C. over30 min. This reaction mixture was stirred at room temperature for 3 hrand was poured into ice water (1000 ml). The mixture was extracted withethyl acetate (200 ml×2). The ethyl acetate layer was washed withaqueous sodium hydroxide and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated to give a mixture (1.4 g)containing N-(2-(4-formylphenyl)ethyl)acetamide andN-(2-(2-formylphenyl) ethyl) acetamide at about 8:1 as a pale-brown oil.

To a solution of this mixture (1.4 g) in ethanol (7.3 ml) was addedsodium borohydride (0.56 g) and the mixture was stirred at 50° C. for 3hr. Thereto was added 2N hydrochloric acid (ca. 20 ml) at below 10° C.This mixture was poured into water (300 ml) and extracted with ethylacetate (250 ml×2). The ethyl acetate layer was washed with aqueoussodium hydroxide (200 ml) and saturated brine (200 ml), and dried overanhydrous sodium sulfate. The solvent was evaporated and the obtainedresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:methanol:chloroform=3:1:12) to give a mixture(0.58 g) containing N-(2-(4-hydroxymethylphenyl)ethyl)-acetamide andN-(2-(2-hydroxymethylphenyl)ethyl)acetamide at about 8:1 as a yellowoil.

A solution of this mixture (0.58 g) and thionyl chloride (0.30 ml) indichloromethane (15 ml) was refluxed under heating for 2 hr. The solventwas evaporated and the obtained residue was purified by silica gelcolumn chromatography (developing solvent; ethyl acetate) to give amixture (0.40 g) containing the title compound andN-(2-(2-chloromethylphenyl)ethyl)acetamide at about 8:1 as whitecrystals.

In the same manner as in the above, white crystals (0.70 g) containingthe title compound and N-(2-(2-chloromethylphenyl)ethyl)acetamide atabout 8:1 was obtained. The crystals were combined with the crystals(0.40 g) obtained earlier and recrystallized from a mixture of ethylacetate-isopropyl ether-hexane to give the title compound (0.58 g) aswhite crystals, m.p.=86-88° C.

¹H-NMR(CDCl₃) δ: 1.94(3H, s), 2.82(2H, dd, J=7.3, 6.6 Hz), 3.50(2H, dd,J=7.3, 6.6 Hz), 4.57(2H, s), 5.49(1H, br.s), 7.19(2H, d, J=8.6 Hz),7.34(2H, d, J=7.9 Hz); IR(KBr): 3297, 1633, 1543 cm⁻¹; MS(EI):211((M+1)+); Elemental analysis: Calculated: C; 62.41, H; 6.67, N; 6.62;Found: C; 62.34, H; 6.80, N; 6.70.

(2) N-(2-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(2-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals, m.p.=117-118° C.

¹H-NMR(CDCl₃) δ: 1.94(3H, s), 2.61(4H, t, J=5.3 Hz), 3.15(2H, dd, J=7.3,6.6 Hz), 3.20(2H, t, J=5.3 Hz), 3.15(2H, dd, J=6.6, 5.9 Hz), 3.55(2H,s), 5.46(1H, br.s), 6.84(1H, t, J=7.3 Hz), 6.92(2H, d, J=7.9 Hz),7.16(1H, d, J=7.9 Hz), 7.23(2H, d, J=7.9 Hz), 7.30(2H, d, J=7.9 Hz);IR(KBr): 3352, 3302, 1647, 1535 cm⁻¹; MS(EI): 337((M−1)+); Elementalanalysis: Calculated: C; 74.74, H; 8.06, N; 12.45; Found: C; 74.49, H;8.05, N; 12.40.

Example 15 Synthesis ofN-(3-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide 1/4Hydrate

(1) N-(3-(4-Chloromethylphenyl)propyl)acetamide

To a solution of N-(3-phenylpropyl)acetamide (10.14 g) indichloromethane (130 ml) was added titanium tetrachloride (28 ml) at5-7° C. over 30 mm. There to was added a solution of dichloromethylmethyl ether (18 ml) in dichloromethane (20 ml) at 5-8° C. over 30 min.This reaction mixture was stirred at room temperature for 3 hr, andpoured into ice water (1000 ml). The mixture was extracted withchloroform (500 ml×2). The chloroform layer was washed with saturatedaqueous sodium hydrogencarbonate, and dried over anhydrous sodiumsulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=2:1→methanol:chloroform=3:97) to give a mixture(10.85 g) containing N-(3-(4-formylphenyl)propyl)acetamide andN-(3-(2-formylphenyl)propyl)acetamide at about 6:1 as a yellow oil.

To a solution of this mixture (10.85 g) in ethanol (100 ml) was addedsodium borohydride (2.0 g) at 5° C. over 15 min. This mixture wasstirred at room temperature for 1 hr and 2N hydrochloric acid (ca. 20ml) was added at below 10° C. This mixture was poured into water (300ml) and extracted with ethyl acetate (250 ml×2). The ethyl acetate layerwas washed with saturated sodium hydrogencarbonate solution (200 ml) andsaturated brine (200 ml), and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the obtained residue was purified by silicagel column chromatography (developing solvent; methanol:chloroform=4:96)to give a mixture (4.36 g) containingN-(3-(4-hydroxymethylphenyl)propyl)acetamide andN-(3-(2-hydroxymethylphenyl)propyl)acetamide at about 6:1 as whitecrystals.

A solution of this mixture (1.428 g) and thionyl chloride (0.60 ml) inchloroform (50 ml) was refluxed under heating for 2 hr. The solvent wasevaporated and the obtained residue was purified by silica gel columnchromatography (developing solvent; methanol:chloroform=3:97) to give amixture (1.26 g) containing the title compound andN-(3-(2-chloromethylphenyl)propyl)acetamide at about 6:1 as whitecrystals. The crystals (0.98 g) were recrystallized from ethylacetate-hexane to give the title compound (0.23 g) as white crystals.m.p.=89-90° C.

¹H-NMR(CDCl₃) δ: 1.82(2H, tt, J=7.4, 7.4 Hz), 1.94(3H, s), 2.65(2H, t,J=7.6 Hz), 3.27(2H, dt, J=6.8 Hz), 4.56(2H, s), 5.55(1H, br.s), 7.17(2H,d, J=8.6 Hz), 7.29(2H, d, J=7.9 Hz); IR(KBr): 3298, 1639, 1551 cm⁻¹;MS(EI): 226((M+1)+); Elemental analysis: Calculated: C; 63.85, H; 7.14,N; 6.21; Found: C; 63.69, H; 7.17, N; 6.20.

(2) N-(3-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide 1/4Hydrate

By similar reaction and treatment to that in Example 1(5) usingN-(3-(4-chloromethylphenyl)propyl)acetamide instead ofN-(4-chloromethylphenylmethyl) acetamide, the title compound wasobtained as white crystals, m.p.=117-118° C.

¹H-NMR(CDCl₃) δ: 1.83(2H, tt, J=7.4, 7.4 Hz), 1.94(3H, s), 2.62(6H, m),3.19(4H, t, J=4.9 Hz), 3.27(2H, dt, J=6.8, 6.8 Hz), 3.53(2H, s),5.48(1H, br.s), 6.84(1H, t, J=7.2 Hz), 6.91(2H, d, J=7.1 Hz), 7.14(2H,d, J=7.9 Hz), 7.25(4H, m); IR(KBr): 3323, 2941, 1641, 1601, 1537 cm⁻¹;MS(EI): 351((M+1)+); Elemental analysis: Calculated: C; 74.23, H; 8.35,N; 11.80; Found: C; 74.27, H; 8.26, N; 11.89.

Example 16 Synthesis ofN-(4-(1-(4-Phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamideDihydrochloride

(1) N-Phenylmethylacetamide

To a solution of benzylamine (98.1 g) in methylene chloride (100 ml) wasadded an aqueous solution (200 ml) of sodium hydroxide (44 g). Whilefurther stirring the mixture, acetyl chloride (78 ml) was added at15-20° C. over 1 hr. This reaction mixture was stirred at roomtemperature for 30 min and extracted with chloroform (100 ml×2). Thechloroform layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give a white solid (160g). The obtained solid was crystallized from hexane: ethyl acetate (2:1,750 ml) to give the title compound (125.7 g) as white crystals,m.p.=61-62° C.

¹H-NMR(CDCl₃) δ: 2.00(3H, s), 4.41(2H, d, J=5.3 Hz), 5.95(1H, br.s),7.20-7.35(5H, m); IR(KBr): 3298, 1645, 1552 cm⁻¹; MS(EI): 149(M⁺);Elemental analysis: Calculated: C; 72.46, H; 7.43, N; 9.39; Found: C;72.40, H; 7.32, N; 9.35.

(2) N-[(4-Acetylphenyl)methyl]acetamide

To a suspension of aluminum chloride (22.3 g) in dichloroethane (40 ml)was added acetylchloride (7.1 ml). Thereto was added a solution ofN-phenylmethylacetamide (10 g) in dichloroethane (20 ml) at 10-15° C.over 20 min. This reaction mixture was stirred at room temperature for 6hr and poured into ice water (100 ml). The mixture was extracted withchloroform (100 ml×3). The chloroform layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a black brown oil (15.5 g). The obtained residue waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=20:1) to give the title compound (6.48 g) as a blackbrown solid.

¹H-NMR(CDCl₃) δ: 2.04(3H, s), 2.57(3H, s), 4.46(2H, d, J=5.9 Hz),6.30(1H, br.s), 7.34(2H, d, J=7.9 Hz), 7.88(2H, d, J=7.9 Hz); MS(EI):191(M⁺);

(3) N-{[4-(1-Hydroxyethyl)phenyl]methyl}acetamide

To a solution of N-[(4-acetylphenyl)methyl]acetamide (6.1 g) in methanol(50 ml) was added sodium borohydride (1.2 g) under ice-cooling. Thisreaction mixture was stirred at 5-7° C. for 2 hr. Thereto was added 2%hydrochloric acid and extracted with ethyl acetate (100 ml×3). The ethylacetate layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a brown oil (6.3 g).The obtained brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give the title compound(5.98 g) as a pale-brown oil, m.p.=61-62° C.

¹H-NMR(CDCl₃) δ: 1.46(3H, d, J=6.6 Hz), 1.97(3H, s), 2.55(1H, br.s),4.35(2H, d, J=5.9 Hz), 4.85(1H, q, J=6.6 Hz), 6.15(1H, br.s), 7.21(2H,d, J=7.9 Hz), 7.31(2H, d, J=7.9 Hz); IR(neat): 3302, 2971, 1651, 1556cm⁻¹; MS(EI): 193(M⁺);

(4) N-{[4-(1-Chloroethyl)phenyl]methyl}acetamide

A solution of N-{[4-(1-hydroxyethyl)phenyl]methyl}acetamide (5.7 g) andthionyl chloride (2.6 ml) in chloroform (50 ml) was refluxed underheating for 1.5 hr. The solvent was evaporated to give a brown oil (6.7g). The obtained brown oil was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=20:1) to givethe title compound (5.5 g) as a pale-brown oil.

¹H-NMR(CDCl₃) δ: 1.83(3H, d, J=7.3 Hz), 2.01(3H, s), 4.40(2H, d, J=4.6Hz), 5.07(1H, q, J=7.3 Hz), 6.12(1H, br.s), 7.26(2H, d, J=8.6 Hz),7.38(2H, d, J=8.6 Hz); MS(EI): 211(M⁺);

(5) N-(4-(1-(4-Phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamideDihydrochloride

In Example 1(5), N-{[4-(1-chloroethyl)phenyl]methyl}acetamide was usedfor reaction instead of N-(4-chloromethylphenylmethyl)acetamide, whichwas followed by treatment with 4M hydrochloric acid-dioxane in ethanolto give the title compound as white crystals.

m.p.=233-235° C. (decomposition); ¹H-NMR(DMSO-d₆) δ: 1.74(3H, d, J=6.6Hz), 1.89(3H, s), 2.80-3.20(4H, m), 3.38(1H, m), 3.65-3.85(3H, m),4.27(2H, d, J=5.9 Hz), 4.51(1H, m), 6.86(1H, t, J=7.3 Hz), 6.96(2H, d,J=7.9 Hz), 7.25(2H, dd, J=7.3, 8.6 Hz), 7.34(2H, d, J=7.9 Hz), 7.65(2H,d, J=7.9 Hz), 8.47(1H, m), 11.71(1H, br.s); IR(KBr): 3296, 3061, 2397,1668, 1542 cm⁻¹; MS(EI): 337(M⁺); Elemental analysis: Calculated: C;61.46, H; 7.12, N; 10.24; Found: C; 61.41, H; 7.20, N; 10.32.

Example 17 Synthesis ofN-((2,6-Dimethyl-4-((4-phenylpiperazin-1-yl)methyl)phenyl)methyl)acetamide1/5 Hydrate

(1) 4-Nitromesitylenic Acid

To a solution of chromic anhydride (40 g) in acetic acid (450 ml) wasadded a solution of nitromesitylene (20 g) in acetic acid (50 ml) at65-70° C. over 20 min. This reaction mixture was stirred at 65-70° C.for 30 min and isopropyl alcohol (45 ml) was added. This reactionmixture was further stirred at 50° C. for 30 min. Water was added to thereaction mixture to make the total amount 500 ml and the mixture wasice-cooled. The precipitated crystals were collected by filtration togive the title compound (13 g) as pale-green crystals.

¹H-NMR(CDCl₃) δ: 2.37(6H, s), 7.89(2H, s); IR(KBr): 2968, 2930, 1696,1602, 1535 cm⁻¹; MS(EI): 195(M⁺)

(2) Ethyl 4-Nitromesitylenate

To a solution of 4-nitromesitylenecarboxylic acid (13 g) in ethanol (50ml) was added a solution of 28% hydrochloric acid-ethanol (50 ml) andthe mixture was refluxed under heating for 2 hr. There action mixturewas concentrated and ethyl acetate was added. The mixture was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=9:1) to give the title compound (7.7 g) aspale-brown crystals.

¹H-NMR(CDCl₃) δ: 1.41(3H, t, J=4 Hz), 2.35(6H, s), 4.40(2H, q, J=4 Hz),7.81(2H, s); IR(KBr): 3077, 2998, 1725, 1606, 1524 cm⁻¹; MS(EI):223(M⁺).

(3) Ethyl 4-Aminomesitylenate

To a solution of ethyl 4-nitromesitylenate (7.7 g) in ethyl acetate (300ml) was added 10% palladium-carbon (3 g) and the mixture was stirred for3.5 hr under a hydrogen atmosphere. The catalyst was filtered off fromthe reaction mixture and the filtrate was washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated to give the title compound (6.6 g) as pale-browncrystals.

¹H-NMR(CDCl₃) δ: 1.37(3H, t, J=4 Hz), 2.20(6H, s), 3.96(2H, br.s),4.32(2H, q, J=4 Hz), 7.66(2H, s); IR(KBr): 3506, 3398, 1692, 1627 cm⁻¹;MS(EI): 193(M⁺).

(4) Ethyl 4-Cyanomesitylenate

To a solution of ethyl 4-aminomesitylenate (6.6 g) in conc. hydrochloricacid (50 ml) was added a solution of sodium sulfite (2.6 g) in water (15ml) at 0-5° C. over 30 min. This reaction mixture was stirred at 0° C.for 1 hr. To this reaction mixture was neutralized by adding sodiumcarbonate and then ethyl acetate (100 ml) was added. To a solution ofcopper cyanide (6.8 g) in water (100 ml) was added potassium cyanide (18g) and the mixture was stirred at 0° C. for 30 min. The above-mentionedreaction mixture was added at 0-5° C. and the mixture was stirred at 0°C. for 1 hr. The reaction mixture was extracted with ethyl acetate,washed with aqueous sodium hydrogencarbonate and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe obtained residue was recrystallized from ethyl acetate-hexane togive the title compound (5.5 g) as pale-brown crystals.

¹H-NMR(CDCl₃) δ: 1.39(3H, t, J=4 Hz), 2.57(6H, s), 4.37(2H, q, J=4 Hz),7.76(2H, s). IR(KBr): 3056, 2222, 1716, 1585 cm⁻¹; MS(EI): 203(M⁺).

(5) 4-Aminomethyl-3,5-dimethylbenzyl Alcohol

To a solution of aluminum lithium hydride (2.1 g) in tetrahydrofuran (20ml) was added a solution of ethyl 4-cyanomesitylenate (2.9 g) intetrahydrofuran (30 ml) at 0° C. and the mixture was refluxed underheating for 6 hr. To this reaction mixture was added 50% (v/v)tetrahydrofuran in water under ice-cooling. This mixture was stirred atroom temperature for 30 min and the catalyst was filtered off usingCelite. The solvent was evaporated and the obtained residue wasrecrystallized from methanol-isopropyl ether to give the title compound(5.5 g) as white crystals.

¹H-NMR(CDCl₃) δ: 1.52(3H, br.s), 2.39(6H, s), 3.85(2H, s), 4.59(2H, s),7.03(2H, s); IR(KBr): 3294, 2927, 2858, 1647, 1554 cm⁻¹; MS(EI):164(M⁺);

(6) N-((4-Hydroxymethyl-2,6-dimethylphenyl)methyl)acetamide

To a solution of 4-aminomethyl-3,5-dimethylbenzyl alcohol (2.3 g) inethyl acetate (70 ml) was added a solution of potassium carbonate (2.0g) in water (35 ml). To this solution was added acetyl chloride (0.95ml) under ice-cooling. This mixture was stirred at room temperature for1 hr. The reaction mixture was extracted with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the obtained residue was recrystallized frommethanol-ethyl acetate to give the title compound (2.0 g) as whitecrystals, m.p.=193.5-194.5° C.

¹H-NMR(CDCl₃) δ: 1.97(3H, s), 2.36(6H, s), 4.44(2H, d, J=4.6 Hz),4.62(2H, s), 5.27(1H, br.s), 7.06(2H, s); IR(KBr): 3286, 2951, 1632,1537 cm⁻¹; MS(EI): 207(M⁺);

(7) N-((4-Chloromethyl-2,6-dimethylphenyl)methyl)acetamide

To a solution of N-((4-hydroxymethyl-2,6-dimethylphenyl)methyl)acetamide(1.0 g) in dichloromethane (12 ml) was added thionyl chloride (0.88 ml).This mixture was stirred at room temperature for 3 hr. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogencarbonate and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated and the obtained residue was recrystallized from ethylacetate-isopropyl ether to give the title compound (1.0 g) as whitecrystals.

m.p.=193-194.5° C. ¹H-NMR(CDCl₃) δ: 1.97(3H, s), 2.36(6H, s), 4.44(2H,d, J=4.6 Hz), 4.50(2H, s), 5.26(1H, br.s), 7.06(2H, s); IR(KBr): 3284,1633, 1538 cm⁻¹; MS(EI): 225(M⁺).

(8)N-(4-(4-Phenylpiperazin-1-ylmethyl)-2,6-dimethylphenylmethyl)acetamide1/5 Hydrate

By similar reaction and treatment to that in Example 1(5) usingN-((4-chloromethyl-2,6-dimethylphenyl)methyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals, m.p.=159-160.5° C.

¹H-NMR(CDCl₃) δ: 1.97(3H, s), 2.36(6H, s), 2.60(4H, dd, J=5.3, 4.6 Hz),3.20(4H, dd, J=5.3, 4.6 Hz), 3.48(2H, s), 4.46(2H, d, J=4.6 Hz),5.27(1H, br.s), 6.86(1H, dt, J=7.3, 1.3 Hz), 6.92(2H, dd, J=7.3, 1.3Hz), 7.04(2H, s), 7.21-7.29(2H, m); IR(KBr): 3269, 2952, 1600, 1546cm⁻¹; MS(EI): 351(M⁺); Elemental analysis: Calculated: C; 74.41, H;8.35, N; 11.83; Found: C; 74.63, H; 8.32, N; 11.79.

Example 18 Synthesis ofN-(4-(4-(4-Fluorophenyl)piperazin-1-ylmethyl)-2,6-dimethylphenylmethyl)acetamide

By similar reaction and treatment to that in Example 17(8) using1-(4-fluorophenyl)piperazine instead of 1-phenylpiperazine, the titlecompound was obtained as white crystals, m.p.=163-164° C.

¹H-NMR(CDCl₃) δ: 1.98(3H, s), 2.36(6H, s), 2.60(4H, dd, J=5.3, 4.6 Hz),3.12(4H, dd, J=5.3, 4.6 Hz), 3.48(2H, s), 4.45(2H, d, J=4.6 Hz),5.25(1H, br.s), 6.83-6.98(4H, m), 7.03(2H, s); IR(KBr): 3323, 2947,1645, 1531 cm⁻¹; MS(EI): 369(M⁺); Elemental analysis: Calculated: C;71.52, H; 7.64, N; 11.37; Found: C; 71.22, H; 7.71, N; 11.28.

Example 19 Synthesis ofN-(4-(1-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamideDihydrochloride

In Example 1(5), N-((4-(1-chloroethyl)phenyl)methyl)acetamide was usedfor reaction instead of N-(4-chloromethylphenylmethyl)acetamide and1-(2-methoxyphenyl)piperazine instead of 1-phenylpiperazine, which wasfollowed by treatment with 4M hydrochloric acid-dioxane in ethanol togive the title compound as white crystals.

m.p.=220-223° C. (decomposition); ¹H-NMR(DMSO-d₆) δ: 1.75(3H, d, J=6.6Hz), 1.90(3H, s), 2.90-3.25(4H, m), 3.40-3.60(3H, m), 3.77(3H, s),3.82(1H, m), 4.28(1H, d, J=5.3 Hz), 4.53(1H, m), 6.85-7.10(4H, m),7.35(2H, d, J=7.9 Hz), 7.68(2H, d, J=8.6 Hz), 8.53(1H, t, J=5.3 Hz),11.81(1H, br.s); IR(KBr): 3286, 3253, 2983, 2404, 1668 cm⁻¹; MS(EI):367(M⁺); Elemental analysis: Calculated: C; 60.00, H; 7.09, N; 9.54;Found: C; 60.07, H; 7.19, N; 9.61.

Example 20 Synthesis ofN-(4-((4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(2,4-difluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as pale-browncrystals, m.p.=94-95° C.

¹H-NMR(CDCl₃) δ: 2.02(3H, s), 2.61(4H, dd, J=5.28, 4.62 Hz), 3.04(4H,dd, J=5.3, 4.6 Hz), 3.56(2H, s), 4.42(2H, d, J=5.9 Hz), 5.71(1H, br.s),6.73-6.93(3H, m), 7.24(2H, d, J=7.9 Hz), 7.32(2H, d, J=7.9 Hz); IR(KBr):3307, 2939, 2821, 1645, 1556 cm⁻¹; MS(EI): 359(M⁺); Elemental analysis:Calculated: C; 66.84, H; 6.45, N; 11.69; Found: C; 66.84, H; 6.43, N;11.66.

Example 21 Synthesis ofN-(2-Nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Methyl 4-Acetamidomethyl-3-nitrobenzoate

To a mixture (mixed acid) of fuming nitric acid (70 ml) and conc.sulfuric acid (70 ml) was added methyl 4-acetamidomethylbenzoate (54 g)at 7-15° C. for 1.5 hr. This reaction mixture was stirred at roomtemperature for 1 hr and poured into ice water (600 ml). The mixture wasextracted with chloroform (300 ml×3). The extract was washed with water,saturated sodium hydrogencarbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated to givea yellow oil (75 g). The obtained yellow oil was crystallized from ethylacetate (50 ml) and recrystallized from hexane/ethyl acetate (1:1, 600ml) to give the title compound (45.5 g) as pale-yellow crystals.

m.p.=100-102° C.; ¹H-NMR(CDCl₃)δ: 2.02(3H, s), 3.97(3H, s), 4.71(2H, d,J=6.6 Hz), 6.38(1H, m), 7.76(1H, d, J=7.9 Hz), 8.24(1H, dd, J=1.3, 7.9Hz), 8.67(1H, d, J=1.3 Hz); IR(KBr): 3280, 1735, 1648, 1533, 1434 cm⁻¹;MS(EI): 253((M+1)+); Elemental analysis: Calculated: C; 52.38, H; 4.80,N; 11.11; Found: C; 52.33, H; 4.79, N; 11.11.

(2) N-(4-Hydroxymethyl-2-nitrophenylmethyl)acetamide

A solution of methyl 4-acetamidomethyl-3-nitrobenzoate (20 g) andlithium borohydride (1.7 g) in tetrahydrofuran (200 ml) was stirred at40-50° C. for 2.5 hr. The reaction mixture was poured into water (150ml) and extracted with ethylacetate (100 ml×3). The extract was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a yellow oil (15.5 g). The obtainedyellow oil was purified by silica gel column chromatography (developingsolvent; chloroform:methanol=9:1) to give a pale-brown solid (13.5 g).The obtained solid was crystallized from ethyl acetate/ethanol/hexane(30:2:5) to give the title compound (12 g) as yellow white crystals.

m.p.=133-135° C.; ¹H-NMR(DMSO-d₆)δ: 1.90(3H, s), 4.51(2H, d, J=5.9 Hz),4.58(2H, d, J=5.3 Hz), 5.47(1H, t, J=5.3 Hz), 7.49(1H, d, J=7.9 Hz),7.64(1H, d, J=7.9 Hz), 7.96(1H, s), 8.39(1H, m) IR(KBr): 3290, 1656,1558, 1529 cm⁻¹; MS(EI): 225((M+1)+).

(3) N-(4-Chloromethyl-2-nitrophenylmethyl)acetamide

To a solution of N-(4-hydroxymethyl-2-nitrophenylmethyl)acetamide (9.1g), triethylamine (6.2 ml) and dimethylaminopyridine (0.99 g) indichloromethane (150 ml)-tetrahydrofuran (50 ml) was addedp-toluenesulfonyl chloride (8.5 g) under ice-cooling. This mixture wasstirred at room temperature for 3 hr. The reaction mixture was washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated to give a yellow oil (15.5 g). The obtainedyellow oil was purified by silica gel column chromatography (developingsolvent; chloroform:methanol=20:1) to give the title compound (12 g) asa pale-brown solid (7.8 g).

¹H-NMR(DMSO-d₆)δ: 1.90(3H, s), 4.52(2H, d, J=5.9 Hz), 4.87(2H, s),7.54(1H, d, J=8.6 Hz), 7.79(1H, dd, J=1.3, 8.6 Hz), 8.12(1H, d, J=1.3Hz), 8.43(1H, m); MS(EI): 243(M⁺).

(4) N-(2-Nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethyl-2-nitrophenylmethyl)acetamide (1.4 g),phenylpiperazine (0.8 ml) and potassium carbonate (0.6 g) indimethylformamide (20 ml) was stirred at 60° C. for 4 hr. The reactionmixture was poured into water (150 ml) and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a pale-yellow solid.The obtained pale-yellow solid was crystallized from ethyl acetate togive the title compound (1.3 g) as pale-yellow white crystals,m.p.=135-136° C.

¹H-NMR(DMSO-d₆) δ: 1.90(3H, s), 2.50-2.60(4H, m), 3.10-3.15(4H, m),3.62(2H, s), 4.51(2H, d, J=5.9 Hz), 6.77(1H, m), 6.91(2H, d, J=7.9 Hz),7.20(2H, m), 7.50(1H, d, J=7.9 Hz), 7.68(1H, dd, J=1.3, 7.9 Hz),7.97(1H, d, J=1.3 Hz), 8.40(1H, t, J=5.9 Hz); IR(KBr): 3251, 3080, 2823,1641, 1599 cm⁻¹; MS(EI): 368(M⁺); Elemental analysis: Calculated: C;65.20, H; 6.57, N; 15.21; Found: C; 65.17, H; 6.58, N; 15.12.

Example 22 Synthesis ofN-(2-Amino-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide

To a solution ofN-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide (0.5g) and water-containing Raney-nickel (0.5 g) in ethanol (8 ml) was addeddropwise hydrazine monohydrate (0.7 ml) and the mixture was refluxedunder heating at room temperature for 1 hr. Raney-nickel was removed bypassing the mixture through Celite and the solvent was evaporated togive a white solid (0.48 g). The obtained white solid was crystallizedfrom hexane/ethyl acetate (1:1, 100 ml) to give the title compound (45.5g) as white crystals, m.p.=148-149° C.

¹H-NMR(DMSO-d₆)δ: 1.85(3H, s), 2.40-2.55(4H, m), 3.05-3.15(4H, m),3.35(2H, s), 4.08(2H, d, J=5.9 Hz), 5.05(2H, s), 6.46(1H, dd, J=1.3,5.9Hz), 6.62(1H, d, J=1.3 Hz), 6.76(1H, t, J=7.3 Hz), 6.89-6.93(3H, m),7.15-7.25(2H, m), 8.21(1H, t, J=5.9 Hz); IR(KBr): 3336, 3239, 2809,1623, 1523 cm⁻¹; MS(EI): 338(M⁺); Elemental analysis: Calculated: C;70.98, H; 7.74, N; 16.55; Found: C; 70.85, H; 7.77, N; 16.33.

Example 23 Synthesis ofN-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)-2-nitrophenylmethyl)acetamide

In Example 21(4), (4-fluorophenyl)piperazine dihydrochloride was usedinstead of phenylpiperazine to give the title compound as yellowcrystals, m.p.=112-114° C.

¹H-NMR(DMSO-d₆)δ: 1.91(3H, s), 2.45-2.55(4H, m), 3.05-3.15(4H, m),3.62(2H, s), 4.52(2H, d, J=5.9 Hz), 6.90-7.00(2H, m), 7.00-7.07(2H, m),7.51(1H, d, J=7.9 Hz), 7.68(1H, dd, J=1.3, 7.9 Hz), 7.97(1H, d, J=1.3Hz), 8.40(1H, t, J-5.9 Hz); IR(KBr): 3253, 2831, 1639, 1562 cm⁻¹;MS(EI): 386(M⁺); Elemental analysis: Calculated: C; 62.16, H; 6.00, N;14.50; Found: C; 61.80, H; 5.97, N; 14.13.

Example 24 Synthesis ofN-(2-Amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

In Example 22,N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-2-nitrophenylmethyl)acetamidewas used instead ofN-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide togive the title compound as yellow white crystals, m.p.=163-164° C.

¹H-NMR(DMSO-d₆)δ: 1.85(3H, s), 2.45-2.55(4H, m), 3.00-3.10(4H, m),3.33(2H, s), 4.08(2H, d, J=6.6 Hz), 5.05(2H, s), 6.46(1H, dd, J=1.3, 7.3Hz), 6.61(1H, d, J=1.3 Hz), 6.89-6.95(3H, m), 6.99-7.06(2H, m), 8.21(1H,t, J=5.9 Hz); IR(KBr): 3311, 3241, 2836, 1626, 1510 cm⁻¹; MS(EI):356(M⁺); Elemental analysis: Calculated: C; 67.39, H; 7.07, N; 15.72;Found: C; 67.56, H; 7.14, N; 15.59.

Example 25 Synthesis ofN-(2-Acetamide-4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution ofN-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(1.65 g), acetic anhydride (0.52 ml) and triethylamine (0.77 ml) inmethylene chloride (20 ml) was refluxed under heating for 3 hr. Thereaction mixture was poured into water (150 ml) and extracted withchloroform. The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated to give a brownoil. The obtained brown oil was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=20:1) to give apale-brown solid (1.5 g). This pale-brown solid was crystallized fromethyl acetate to give the title compound (1.1 g) as pale-yellowcrystals, m.p.=145-146° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 2.07(3H, s), 2.45-2.55(4H, m),3.00-3.10(4H, m), 3.47(2H, s), 4.20(2H, d, J=5.9 Hz), 6.88-6.98(2H, m),6.99-7.07(3H, m), 7.20(1H, d, J=7.9 Hz), 7.66(1H, s), 8.48(1H, t, J=5.9Hz), 9.82(1H, s); IR(KBr): 3288, 2819, 1673, 1626, 1587 cm⁻¹; MS(EI):398(M⁺); Elemental analysis: Calculated: C; 66.31, H; 6.83, N; 14.06;Found: C; 66.06, H; 6.78, N; 13.94.

Example 26 Synthesis ofN-(2-Chloro-4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

To an aqueous solution (2 ml) of sodium nitrite (213 mg) was added asolution ofN-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(1.1 g) in conc. hydrochloric acid (5 ml) under ice-cooling. Thismixture was stirred at the same temperature for 40 min. The reactionmixture was added to a solution of copper(I) chloride (183 mg) in conc.hydrochloric acid (2 ml) over 10 min. The mixture was stirred at roomtemperature for 2 hr. The reaction mixture was poured into aqueoussodium hydroxide solution and extracted with ethyl acetate. The extractwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated to give a green oil (1.4 g). The obtainedgreen oil was purified by silica gel column chromatography (developingsolvent ; chloroform:methanol=20:1) to give a pale-brown solid (0.9 g).This pale-brown solid was crystallized from ethyl acetate/hexane to givethe title compound (0.75 g) as yellow crystals.

m.p.=141-142° C.; ¹H-NMR(DMSO-d₆)δ: 1.90(3H, s), 2.45-2.55(4H, m),3.00-3.10(4H, m), 3.51(2H, s), 4.30(2H, d, J=5.9 Hz), 6.85-6.95(2H, m),6.95-7.05(2H, m), 7.22-7.32(2H, m), 7.38(1H, s), 8.32(1H, t, J=5.9 Hz);IR(KBr): 3267, 2827, 1653, 1554, 1512 cm⁻¹; MS(EI): 375(M⁺); Elementalanalysis: Calculated: C; 63.91, H; 6.17, N; 11.18; Found: C; 63.85, H;6.16, N; 11.23.

Example 27 Synthesis ofN-(2-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) 4-((4-Chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine

To an aqueous solution (100 ml) of 1-(4-fluorophenyl)piperazinedihydrochloride was added an aqueous solution (50 ml) of sodiumhydroxide (10 g) and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a white solid (ca. 20g). A solution of this solid (1-(4-fluorophenyl)piperazine),α,α′-dichloro-p-xylene (20.0 g) and potassium carbonate indimethylformamide (150 ml) was stirred at 75° C. for 2 hr and pouredinto ice water (500 ml). The mixture was extracted with ethyl acetate(400 ml×2). The ethyl acetate layer was washed with saturated brine anddried over anhydrous sodium sulfate. The obtained residue was purifiedby silica gel column chromatography (developing solvent; ethylacetate:hexane=1:3) and recrystallized from ethyl acetate-hexane to givethe title compound (10.66 g) as white crystals.

m.p.=81-83° C.; ¹H-NMR(CDCl₃)δ: 2.60(4H, t, J=5.3 Hz), 3.11(4H, t, J=4.9Hz), 3.56(2H, s), 4.58(2H, s), 6.90(4H, m), 7.35(4H, s); IR(KBr): 2947,2839, 2773, 1514 cm⁻¹; MS(EI): 318(M⁺); Elemental analysis: Calculated:C; 67.81, H; 6.32, N; 8.79; Found: C; 67.80, H; 6.34, N; 8.75.

(2) 2-(4-(4-(4-Fluorophenyl)piperazin-1-ylmethyl)phenyl)acetonitrile

A solution of4-((4-chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine (10.0 g),sodium cyanide (1.72 g) and a catalytic amount of sodium iodide indimethylformamide (50 ml) was stirred at 70° C. for 3 hr, and pouredinto ice water (200 ml) and extracted with ethyl acetate (300 ml×2). Theethyl acetate layer was washed with saturated brine and dried overanhydrous sodium sulfate. The obtained residue was purified by silicagel column chromatography (developing solvent; ethyl acetate:hexane=1:2)and recrystallized from ethyl acetate-hexane to give the title compound(6.50 g) as pale-yellow crystals.

m.p.=111-113° C.; ¹H-NMR(CDCl₃)δ: 2.60(4H, t, J=5.0 Hz), 3.11(4H, t,J=4.9 Hz), 3.56(2H, s), 3.73(2H, s), 6.89(4H, m), 7.29(2H, d, J=7.9 Hz),7.37(2H, d, J=7.9 Hz); IR(KBr): 2946, 2816, 2775, 2248, 1514 cm⁻¹;MS(EI): 291((M−F)+); Elemental analysis: Calculated: C; 73.76, H; 6.52,N; 13.58; Found: C; 73.98, H; 6.52, N; 13.52.

(3)N-(2-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

To a solution of aluminum lithium hydride (0.74 g) in tetrahydrofuran(30 ml) was added2-(4-(4-(4-fluorophenyl)-piperazin-1-ylmethyl)phenyl)acetonitrile (2.0g) in tetrahydrofuran (30 ml) at 5-10° C., and the mixture was refluxedunder heating for 4 hr. To this reaction mixture was added saturatedaqueous sodium sulfate solution (10 ml) under ice-cooling. The insolublematter was filtered off and the solvent was evaporated to give theobtained residue as purified by silica gel column chromatography(developing solvent; ethyl acetate:hexane=3:1; methanol:chloroform=1:9,later 1:6) to give4-(4-(2-aminoethyl)phenyl)-1-(4-fluorophenyl)piperazine (0.59 g). Tothis compound in a dichloromethane solution (20 ml) were addedtriethylamine (0.24 ml) and acetic anhydride (0.21 ml) and the mixturewas left standing at room temperature for 10 min and poured into icewater (100 ml) and extracted with ethyl acetate (100 ml×2). The ethylacetate layer was washed with saturated brine (100 ml) and dried overanhydrous sodium sulfate. The obtained crude crystals wererecrystallized from ethyl acetate/hexane to give the title compound (416mg) as pale-brown crystals, m.p.=121-123° C.

¹H-NMR(CDCl₃)δ: 1.94(3H, s), 2.61(4H, t, J=5.0 Hz), 2.81(2H, t, J=6.9Hz), 3.12(4H, t, J=4.9 Hz), 3.51(2H, q, J=6.4 Hz), 3.54(2H, s), 5.50(1H,br.s), 6.89(4H, m), 7.16(2H, d, J=7.9 Hz), 7.29(2H, d, J=7.9 Hz);IR(KBr): 3292, 2819, 1647, 1514 cm⁻¹; MS(EI): 355(M⁺); Elementalanalysis: Calculated: C; 70.96, H; 7.37, N; 11.82; Found: C; 70.81, H;7.41, N; 11.68.

Example 28 Synthesis ofN-(2-Bromo-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

To an aqueous solution (4 ml) of sodium nitrite (387 mg) was added asolution ofN-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(2.0 g) in 48% hydrobromic acid (10 ml) under ice-cooling. This reactionmixture was stirred at the same temperature for 45 min and added to asolution of copper(I) bromide (483 mg) in 48% hydrobromic acid (6 ml)over 15 min. This reaction mixture was stirred at room temperature for 5hr and poured into aqueous sodium hydroxide solution. The mixture waspassed through Celite and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a brown oil (1.7 g). The obtained brownoil was purified by silica gel column chromatography (developingsolvent; chloroform:methanol=20:1) to give a brown oil (1.4 g). Thisbrown oil was crystallized from ethyl acetate-hexane and recrystallizedfrom ethyl acetate-hexane to give the title compound (0.9 g) as yellowwhite crystals, m.p.=149-150° C.

¹H-NMR(DMSO-d₆)δ: 1.91(3H, s), 2.45-2.55(4H, m), 3.00-3.10(4H, m),3.50(2H, s), 4.27(2H, d, J=5.9 Hz), 6.85-6.95(2H, m), 6.95-7.05(2H, m),7.22-7.35(2H, m), 7.55(1H, s), 8.33(1H, t, J=5.9 Hz); IR(KBr): 3269,2827, 1653, 1550, 1512 cm⁻¹; MS(EI): 420(M⁺); Elemental analysis:Calculated: C; 57.15, H; 5.52, N; 10.00; Found: C; 56.92, H; 5.39, N;9.92.

Example 29 Synthesis ofN-(3-Nitro-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

(1) 4-Methyl-3-nitrobenzonitrile

To conc. sulfuric acid (50 ml) was added p-tolunitrile (50 g) underice-cooling and fuming nitric acid (38 ml) was added at the sametemperature over 1 hr. The reaction mixture was poured into ice water(700 g) and the precipitated crystals were collected by filtration. Theobtained crystals were washed with water to give yellow white crystals(90 g). The yellow white crystals were recrystallized from ethanol:water(9:1) to give the title compound (61 g) as white crystals.

m.p.=102-103° C.; ¹H-NMR(DMSO-d₆)δ: 2.58(3H, s), 7.73(1H, d, J=7.9 Hz),8.09(1H, dd, J=1.3, 7.9 Hz), 8.50(1H, d, J=1.3 Hz); IR(KBr): 3088, 2235,1616, 1525 cm⁻¹; MS(EI): 163(M⁺); Elemental analysis: Calculated: C;59.26, H; 3.73, N; 17.28; Found: C; 59.05, H; 3.53, N; 16.86.

(2) 4-Bromomethyl-3-nitrobenzonitrile

A solution of 4-methyl-3-nitrobenzonitrile (30 g), N-bromosuccinimide(37 g) and azobisisobutyronitrile (3.1 g) in carbon tetrachloride (300ml) was refluxed under heating for 8 hr. To the reaction mixture wasadded water (100 ml) and the mixture was extracted with chloroform. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theobtained residue was purified by silica gel column chromatography(developing solvent; ethyl acetate:hexane=1:4) and recrystallized fromethyl acetate-hexane to give the title compound (23.7 g) as pale-yellowcrystals, m.p.=85-89° C.

¹H-NMR(DMSO-d₆)δ: 4.96(2H, s), 7.97(1H, d, J=7.9 Hz), 8.22(1H, dd,J=1.3, 7.9 Hz), 8.61(1H, d, J=1.3 Hz); IR(KBr): 3082, 2235, 1614, 1530cm⁻¹; MS(EI): 241(M⁺); Elemental analysis: Calculated: C; 39.86, H;2.09, N; 11.62; Found: C; 40.64, H; 2.15, N; 11.85.

(3) N-(4-Bromomethyl-3-nitrophenylmethyl)acetamide

To a solution of 4-bromomethyl-3-nitrobenzonitrile (25.7 g) intetrahydrofuran (250 ml) was added a 2.0 M tetrahydrofuran solution (59ml) of a borane-methylsulfide complex and the mixture was refluxed underheating for 4.5 hr. To the reaction mixture was added hydrochloricacid-methanol and the mixture was refluxed under heating for 1.5 hr. Thesolvent was evaporated under reduced pressure to give a brown oil. Theobtained brown oil was crystallized from ethyl acetate to give yellowwhite crystals. To a mixed solution of the obtained yellow whitecrystals, acetic anhydride (12.1 ml), water (50 ml) and ethyl acetate(100 ml) was added an aqueous solution (50 ml) of sodium hydroxide (12.8g) under ice-cooling. This reaction mixture was stirred at roomtemperature for 2.5 hr and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=20:1) to give the title compound (21.4 g) as a brownoil.

¹H-NMR(CD3OD)δ: 2.03(3H, s), 4.45(2H, s), 4.94(2H, d, J=2.0 Hz),7.55-7.65(2H, m), 7.96(1H, s); MS(EI): 287(M⁺).

(4)N-(3-Nitro-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

A solution of N-(4-bromomethyl-3-nitrophenylmethyl)acetamide (21 g),1-(4-fluorophenyl)piperazine dihydrochloride (20.4 g) and potassiumcarbonate (40.4 g) in dimethylformamide (200 ml) was stirred at 85° C.for 8.5 hr. The reaction mixture was poured into water (300 ml) andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a brown oil (37 g). The obtained residue was purifiedby silica gel column chromatography (developing solvent; ethylacetate:hexane=1:1) to give a brown oil (15.5 g). To a solution of thisbrown oil (1.0 g) in ethanol (20 ml) was added 1M hydrochloricacid-ether (6.5 ml). The solvent was evaporated under reduced pressure.The residue was crystallized from ethanol-ethyl acetate to give thetitle compound (1.1 g) as pale-brown crystals.

m.p.=202-204° C. (decomposition); ¹H-NMR(DMSO-d₆)δ: 1.92(3H, s),3.20-3.50(8H, m), 4.39(2H, d, J=5.9 Hz), 4.70(2H, s), 4.70-4.90(2H,brs), 6.95-7.15(4H, m), 7.75(1H, m), 8.05-8.10(2H, m), 8.72(1H, t, 5.9Hz); IR(KBr): 3255, 2337, 2157, 1627, 1537 cm⁻¹; MS(EI): 241(M⁺);Elemental analysis: Calculated: C; 51.29, H; 5.60, N; 11.96; Found: C;51.56, H; 5.58, N; 11.91.

Example 30 Synthesis ofN-(3-Amino-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

To a solution ofN-(3-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide(14.5 g) and water-containing Raney-nickel (5.0 g) in ethanol (150 ml)was added dropwise hydrazine monohydrate (18.2 ml) at room temperatureand the mixture was refluxed under heating for 4 hr. Raney-nickel wasremoved by passing the mixture through Celite and the solvent wasevaporated to give a brown oil (18.0 g). The obtained brown oil waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=20:1) to give a brown oil (11.6 g). The obtainedbrown oil was crystallized from hexane:ethyl acetate (2:1) to give thetitle compound (7.4 g) as yellow white crystals.

m.p.=131-132° C.; ¹H-NMR(DMSO-d₆)δ: 1.86(3H, s), 2.45-2.55(4H, m),3.05-3.10(4H, m), 3.40(2H, s), 4.11(2H, d, J=5.9 Hz), 5.25(2H, s),6.41(1H, dd, J=1.3, 5.9 Hz), 6.53(1H, d, J=1.3 Hz), 6.88-6.95(3H, m),7.00-7.06(2H, m), 8.20(1H, t, J=5.3 Hz); IR(KBr): 3305, 2819, 1625, 1512cm⁻¹; MS(EI): 356(M⁺); Elemental analysis: Calculated: C; 67.39, H;7.07, N; 15.72; Found: C; 67.06, H; 7.19, N; 15.40.

Example 31 Synthesis ofN-(3-Chloro-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

To an aqueous solution (2 ml) of sodium nitrite (213 mg) was added asolution ofN-(3-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(1.0 g) in conc. hydrochloric acid (5 ml) under ice-cooling. Thisreaction mixture was stirred at the same temperature for 1 hr and addedto a solution of copper(I) chloride (167 mg) in conc. hydrochloric acid(3 ml). The reaction mixture was stirred at room temperature for 3 hr,poured into an aqueous sodium hydroxide solution and extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate and the solvent was evaporated to give abrown oil (1.4 g). The obtained brown oil was purified by silica gelcolumn chromatography (developing solvent; chloroform:methanol=10:1) togive a brown oil (1.2 g). The brown oil was treated with 1M hydrochloricacid-ether (10 ml) in ethanol and concentrated under reduced pressure togive a brown solid. The obtained brown solid was crystallized from ethylacetate-ethanol to give the title compound (0.7 g) as pale-yellowcrystals, m.p.=200-205° C. (decomposition).

¹H-NMR(DMSO-d₆)δ: 1.91(3H, s), 3.10-3.50(6H, m), 3.60-3.70(2H, m),4.29(2H, d, J=5.9 Hz), 4.51(2H, s), 4.90-5.10(2H, m), 6.95-7.15(4H, m),7.33(1H, d, J=7.3 Hz), 7.45(1H, s), 8.00(1H, d, J=7.9 Hz), 8.60(1H, t,J=5.9 Hz), 11.69(1H, brs); IR(KBr): 3282, 2493, 2443, 2418, 2063, 1676,1542 cm⁻¹; MS(EI): 376(M⁺); Elemental analysis: Calculated: C; 52.47, H;5.72, N; 9.18; Found: C; 52.76, H; 5.57, N; 9.58.

Example 32 Synthesis ofN-(3-Bromo-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

To an aqueous solution (3 ml) of sodium nitrite (290 mg) was added asolution ofN-(3-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(1.5 g) in 48% hydrobromic acid (8 ml) under ice-cooling. This reactionmixture was stirred at the same temperature for 45 min and added to asolution of copper(I) bromide (362 mg) in 48% hydrobromic acid (4 ml)over 15 min. The reaction mixture was stirred at room temperature for4.5 hr and poured into an aqueous sodium hydroxide solution. Afterpassing through Celite, the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate and the solvent was evaporated to give a brown solid (1.8g). The obtained brown solid was crystallized from ethyl acetate to givethe title compound (1.3 g) as yellow crystals, m.p.=125-127° C.

¹H-NMR(DMSO-d₆)δ: 1.88(3H, s), 2.50-2.60(4H, m), 3.05-3.10(4H, m),3.57(2H, s), 4.23(2H, d, J=5.9 Hz), 6.85-6.95(2H, m), 6.95-7.05(2H, m),7.25(1H, dd, J=1.3, 7.9 Hz), 7.44(1H, d, J=7.9 Hz), 7.48(1H, d, J=1.3Hz), 8.36(1H, t, J=5.9 Hz); IR(KBr): 3304, 2823, 1649, 1508 cm⁻¹;MS(EI): 420(M⁺); Elemental analysis: Calculated: C; 57.15, H; 5.52, N;10.00; Found: C; 57.15, H; 5.54, N; 10.05.

Example 33 Synthesis ofN-(4-((4-(4-Nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(4-nitrophenyl)piperazine instead of phenylpiperazine, the titlecompound was obtained as yellow crystals, m.p.=151.5-153.5° C.

¹H-NMR(CDCl₃)δ: 2.03(3H, s), 2.58(4H, dd, J=5.3, 4.6 Hz), 3.42(4H, dd,J=5.3, 4.6 Hz), 3.55(2H, s), 4.42(2H, d, J=5.9 Hz), 5.77(1H, br.s),6.80(2H, d, J=9.9 Hz), 7.25(2H, d, J=7.9 Hz), 7.31(2H, d, J=7.9 Hz),8.16(2H, d, J=9.2 Hz). IR(KBr): 3307, 2922, 2848, 1641, 1540 cm⁻¹;MS(EI): 368(M⁺); Elemental analysis: Calculated: C; 65.20, H; 6.57, N;15.21; Found: C; 65.06, H; 6.58, N; 15.19.

Example 34 Synthesis ofN-(4-((4-(4-Aminophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide 3Hydrochloride 3/2 Hydrate

To a solution ofN-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(6.1 g) and Raney-nickel (0.6 g) in ethanol (166 ml) was added dropwisehydrazine monohydrate (4 ml) at 2° C.-3° C. over 30 min. This reactionmixture was stirred at room temperature for 1 hr, then at 35° C. for 30min, and subsequently refluxed under heating at 50° C. for 6 hr and 40min. To this solution was again added hydrazine monohydrate (4 ml) andthe mixture was refluxed under stirring at 50° C. for 8 hr. The reactionmixture was passed through Celite and the filtrate was concentratedunder reduced pressure and the residue was poured into water, which wasfollowed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate and thesolvent was evaporated to give a purple solid (5.0 g). To the obtainedsolid were added methanol and hydrochloric acid, and the mixture wasconcentrated to dryness under reduced pressure. The obtained solid wasrecrystallized from methanol-ethyl acetate to give the title compound(1.3 g) as purple crystals.

m.p.=198-200° C.; ¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.05-3.40(6H, m),3.75-3.85(2H, m), 4.28(2H, d, J=5.9 Hz), 4.34(2H, s), 7.06(2H, d, J=8.6Hz), 7.29(2H, d, J=7.9 Hz), 7.33(2H, d, J=8.6 Hz), 7.62(2H, d, J=7.9Hz), 8.47(1H, t, J=5.9 Hz), 10.30(3H, br.s), 11.61(1H, br.s). IR(KBr):3437, 3278, 2985, 2846, 1626, 1560 cm⁻¹; MS(EI): 338(M⁺); Elementalanalysis: Calculated: C; 50.59, H; 6.86, N; 11.80; Found: C; 50.62, H;6.69, N; 11.79.

Example 35 Synthesis ofN-(4-((4-(4-Acetamidophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

To a-solution ofN-(4-((4-(4-aminophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(1.8 g) and potassium carbonate (3.1 g) in a mixed solvent of water (50ml) and ethyl acetate (50 ml) was added dropwise acetyl chloride (0.43ml) at room temperature over 10 min. This reaction mixture was stirredat room temperature for 4 hr and poured into saturated brine, which wasfollowed by extraction with chloroform. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate and thesolvent was evaporated to give a purple solid (5.0 g). The obtainedsolid was subjected to column chromatography (elution solvent;chloroform:methanol=9:1) to give a pale-brown solid. The solid wasrecrystallized from methanol-water to give the title compound (0.75 g)as pale-red crystals, m.p.=225-226° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 1.98(3H, s), 2.46-2.51(4H, m),3.03-3.06(4H, m), 3.48(2H, s), 4.23(2H, d, J=5.9 Hz), 6.84(2H, d, J=8.6Hz), 7.20(2H, d, J=8.6 Hz), 7.27(2H, d, J=7.9 Hz), 7.39(2H, d, J=9.2Hz), 8.29(1H, t, J=5.9 Hz), 9.66(1H, s). IR(KBr): 3311, 2933, 2819,1655, 1516 cm⁻¹; MS(EI): 380(M⁺); Elemental analysis: Calculated: C;69.45, H; 7.42, N; 14.73; Found: C; 69.19, H; 7.48, N; 14.68.

Example 36 Synthesis ofN-(4-((4-(4-Hydroxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

To a solution ofN-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide(2.0 g) in methylene chloride (27 ml) was added dropwise a solution ofboron tribromide (2.2 ml) in methylene chloride (10 ml) at −70° C. over15 min. The temperature of this solution was gradually raised and themixture was left standing overnight at room temperature. The reactionmixture was poured into ice water and stirred at 40° C. for 30 min.After the reaction, the reaction mixture was neutralized by adding anaqueous sodium hydroxide solution and extracted with chloroform. Theextract was dried over anhydrous sodium sulfate and the solvent wasevaporated to give a brown solid (1.6 g). The obtained solid wassubjected to column chromatography (elution solvent;chloroform:methanol=8:1) to give a pale-brown solid (1.4 g). This solidwas dissolved in methanol and converted to hydrochloride with 1 Mhydrochloric acid-ether solution. The solvent was evaporated and theresidue was recrystallized from methanol-ether to give the titlecompound (0.81 g) as white crystals, m.p.=218-220° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.15-3.80(8H, m), 4.28(2H, d, J=5.9 Hz),4.35(2H, s), 6.72(2H, d, J=9.2 Hz), 6.93(2H, d, J=8.5 Hz), 7.33(2H, d,J=7.9 Hz), 7.60(2H, d, J=9.2 Hz), 8.44(1H, t, J=5.9 Hz), 11.30(1H,br.s). IR(KBr): 3367, 2987, 2628, 1637, 1552, 1517 cm⁻¹; MS(EI):339(M⁺); Elemental analysis: Calculated: C; 58.25, H; 6.60, N; 10.19;Found: C; 57.88, H; 6.71, N; 9.90.

Example 37 Synthesis ofN-(4-((4-(4-Fluoro-2-nitrophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Synthesis of 1-Acetyl-4-(4-fluoro-2-nitrophenyl)piperazine

To a solution of 1-acetylpiperazine (48 g) in acetonitrile (100 ml) wereadded 2,5-difluoronitrobenzene (50 g) and potassium carbonate (44 g) andthe mixture was refluxed under heating for 5 hr. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfateand the solvent was evaporated to give the title compound (88 g) as ared solid.

¹H-NMR(CDCl₃)δ: 2.13(3H, s), 2.98-3.03(4H, m), 3.61(2H, dd, J=5.28, 4.62Hz), 3.76(2H, dd, J=5.28, 4.62 Hz), 7.17-7.31(2H, m), 7.53(1H, dd,J=7.91, 3.30 Hz). IR(KBr): 3087, 2918, 2835, 1633, 1583 cm⁻¹; MS(EI):267(M⁺);

(2) Synthesis of 1-(4-Fluoro-2-nitrophenyl)piperazine

To 1-acetyl-4-(4-fluoro-2-nitrophenyl)piperazine (10 g) was added 1.2Nhydrochloric acid (190 ml) and the mixture was refluxed under heatingfor 17 hr. The reaction mixture was made alkaline (pH 12) with anaqueous sodium hydroxide solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give a red oil. The oilwas crystallized from ethyl acetate-isopropyl ether-hexane to give thetitle compound (5.6 g) as a red solid.

m.p.=85-87° C.; ¹H-NMR(CDCl₃)δ: 2.96-3.04(8H, m), 7.15-7.29(2H, m),7.49(1H, dd, J=7.9, 3.3 Hz). IR(KBr): 3325, 2954, 2815, 1520, 1456 cm⁻¹;MS(EI): 225(M⁺); Elemental analysis: Calculated: C; 53.33, H; 5.37, N;18.66; Found: C; 53.44, H; 5.40, N; 18.47.

(3) Synthesis ofN-(4-((4-(4-Fluoro-2-nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluoro-2-nitrophenyl)piperazine instead of phenylpiperazine, thetitle compound was obtained as white crystals, m.p.=94.5-96° C.

¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.58(4H, t, J=4.6 Hz), 3.02(4H, t, J=4.6Hz), 3.55(2H, s), 4.42(2H, d, J=5.3 Hz), 5.76(1H, br.s), 7.14-7.22(2H,m), 7.24(2H, d, J=7.9 Hz), 7.30(2H, d, J=9.2 Hz), 7.48(1H, dd, J=7.9,2.6 Hz). IR(KBr): 3277, 2943, 2821, 1645, 1529 cm⁻¹; MS(EI): 386(M⁺);Elemental analysis: Calculated: C; 62.16, H; 6.00, N; 14.50; Found: C;62.15, H; 5.90, N; 14.40.

Example 38 Synthesis ofN-(4-((4-(2-Amino-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 34 usingN-(4-((4-(4-fluoro-2-nitrophenyl)piperazin-1-yl)methyl)-phenylmethyl)acetamideinstead ofN-(4-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide,the title compound was obtained as pale-brown crystals, m.p.=139-140° C.

¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.58(2H, br.s), 5.87(4H, t, J=4.6 Hz),3.56(2H, s), 4.11(2H, br.s), 5.73(1H, br.s), 6.36-6.44(2H, m), 6.93(2H,dd, J=7.9, 5.9 Hz), 7.24(2H, d, J=7.9 Hz), 7.32(2H, d, J=7.9 Hz).IR(KBr): 3444, 3302, 2829, 1662, 1560 cm⁻¹; MS(EI): 356(M⁺); Elementalanalysis: Calculated: C; 67.39, H; 7.07, N; 15.72; Found: C; 67.34, H;7.08, N; 15.64.

Example 39 Synthesis ofN-(4-((4-(2-Acetylamino-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 35 usingN-(4-((4-(2-amino-4-fluorophenyl)piperazin-1-yl)methyl)-phenylmethyl)acetamideinstead ofN-(4-((4-(4-aminophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide,the title compound was obtained as white crystals, m.p.=148-149.5° C.

¹H-NMR(CDCl₃)δ: 2.03(3H, s), 2.20(3H, s), 2.61(4H, br.s), 2.84(4H, t,J=4.6 Hz), 3.57(2H, s), 4.43(2H, d, J=5.9 Hz), 5.77(1H, br.s), 6.72(1H,dt, J=8.6, 2.6 Hz), 7.11(1H, dd, J=8.6, 5.9 Hz), 7.25(2H, d, J=7.9 Hz),7.32(2H, d, J=7.9 Hz), 8.16(1H, dd, J=11, 2.6 Hz), 8.62(1H, br.s).IR(KBr): 3348, 2935, 2829, 1660, 1603, 1552 cm⁻¹; MS(EI): 398(M⁺);Elemental analysis: Calculated: C; 66.31, H; 6.83, N; 14.16; Found: C;66.31, H; 6.92, N; 13.87.

Example 40 Synthesis ofN-(4-((4-(4-Fluoro-2-methoxyphenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/4 Hydrate

(1) Synthesis of 4-Fluoro-2-methoxynitrobenzene

To a suspension of sodium hydride (1.3 g) in dimethylformamide (10 ml)was added a solution of 5-fluoro-2-nitrophenol (5.0 g) indimethylformamide (20 ml)under ice-cooling. This reaction mixture wasstirred at room temperature for 1 hr. To this solution was added methyliodide (2.0 ml) and the mixture was left standing overnight. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with an aqueous sodium hydroxide solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated to give a red solid. This solid was subjected to silicagel column chromatography (developing solvent; hexane:ethyl acetate=4:1)to give the title compound (4.3 g) as a yellow solid.

¹H-NMR(CDCl₃)δ: 3.97(3H, s), 6.69-6.82(2H, m), 7.96(1H, dt, J=3.3, 2.6Hz). IR(KBr): 3124, 3086, 2994, 1624, 1587 cm⁻¹; MS(EI): 171(M⁺).

(2) Synthesis of 4-Fluoro-2-methoxyaniline

To a solution of 4-fluoro-2-methoxynitrobenzene (4.2 g) in ethanol (50ml) was added Raney-nickel (0.4 g) at room temperature. To this solutionwas added dropwise hydrazine monohydrate (6 ml) under ice-cooling. Thisreaction mixture was stirred at room temperature for 1 hr and passedthrough Celite. The solvent was evaporated to give an oil. The oil waspoured into water and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfateand the solvent was evaporated to give a brown oil. The oil wassubjected to silica gel column chromatography (developing solvent;hexane:ethyl acetate=1:1) to give the title compound (3.1 g) as a brownoil.

¹H-NMR(CDCl₃)δ: 3.51(2H, br.s), 3.82(3H, s), 6.45-6.64(3H, m). IR(KBr):3452, 3369, 2964, 1612, 1514 cm⁻¹; MS(EI): 141(M⁺).

(3) Synthesis of 1-(4-Fluoro-2-methoxyphenyl)piperazine Dihydrochloride

To a solution of 4-fluoro-2-methoxyaniline (3.0 g) in orthoxylene (50ml) was added bis(2-chloroethyl)amine hydrochloride (3.8 g) and themixture was refluxed under heating for 13 hr. The reaction mixture waspoured into water and washed with isopropyl ether. To the aqueous layerwas added an aqueous sodium hydroxide solution to make it alkaline (pH12) and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfateand the solvent was evaporated to give a black oil. The oil wasdissolved in methanol and conc. hydrochloric acid was added and themixture was concentrated. To this concentrated solution addedtetrahydrofuran to give the title compound (3.1 g) as pale-purplecrystals.

¹H-NMR(DMSO-d₆)δ: 3.20(8H, br.s), 3.82(3H, s), 6.72(1H, dt, J=8.6, 3.3Hz), 6.92(1H, dd, J=11, 3.3 Hz), 7.01(1H, dd, J=8.6, 5.9 Hz), 9.51(2H,br.s). IR(KBr): 3352, 2997, 2808, 1625, 1510 cm⁻¹; MS(EI): 210(M⁺).

(4) Synthesis of N-(4-((4-(4-Fluoro-2-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide Dihydrochloride 1/4 Hydrate

By similar reaction and treatment to that in Example 1(5) using1-(4-fluoro-2-methoxyphenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as white crystals,m.p.=228-229.5° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.06-3.20(4H, m), 3.26-3.43(4H, m),3.79(3H, s), 4.28(2H, d, J=5.9 Hz), 4.33(2H, d, J=2.6 Hz), 6.70(1H, dt,J=8.6, 2.6 Hz), 6.87-6.95(2H, m), 7.33(2H, d, J=7.9 Hz), 7.62(2H, d,J=7.9 Hz), 7.45(1H, t, J=5.9 Hz), 11.5(1H, br.s). IR(KBr): 3286, 2368,1664, 1624, 1539 cm⁻¹; MS(EI): 371(M⁺); Elemental analysis: Calculated:C; 56.19, H; 6.40, N; 9.36; Found: C; 56.04, H; 6.66, N; 9.35.

Example 41 Synthesis ofN-(4-((4-(2-Ethoxy-4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Synthesis of 2-Ethoxy-4-fluoronitrobenzene

To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml) was added asolution of triphenylphosphine (13 g) and 5-fluoro-2-nitrophenol (10 g)in tetrahydrofuran (65 ml). To this solution was added diethylazodicarboxylate (10 ml) under ice-cooling and the mixture was stirredat room temperature for 4 hr. The reaction mixture was concentratedunder reduced pressure and diisopropyl ether was added. The precipitatedcrystals were collected by filtration and concentrated under reducedpressure. The concentrate was subjected to silica gel columnchromatography (developing solvent; hexane:ethyl acetate=4:1) to give ayellow oil. To this oil was added ethyl acetate, washed with an aqueoussodium hydroxide solution, dried over magnesium sulfate and concentratedunder reduced pressure to give the title compound (9.6 g) as a yellowoil.

¹H-NMR(CDCl₃)δ: 1.50(3H, t, J=7.3 Hz), 4.17(2H, q, J=7.3 Hz),6.67-6.79(2H, m), 7.92(1H, dt, J=3.3, 2.6 Hz). MS(EI): 185(M⁺).

(2) Synthesis of 2-Ethoxy-4-fluoroaniline

By similar reaction and treatment to that in Example 40(2) using2-ethoxy-4-fluoronitrobenzene instead of 4-fluoro-2-methoxynitrobenzene,the title compound was obtained as a black oil.

¹H-NMR(CDCl₃)δ: 1.44(3H, t, J=7.3 Hz), 3.50(2H, br.s), 4.00(2H, q, J=7.3Hz), 6.27-6.64(3H, m). IR(KBr): 3548, 3369, 2981, 1618, 1512 cm⁻¹;MS(EI): 155(M⁺).

(3) Synthesis of 1-(2-Ethoxy-4-fluorophenyl)piperazine Dihydrochloride

By similar reaction and treatment to that in Example 40(3) using2-ethoxy-4-fluoroaniline instead of 4-fluoro-2-methoxyaniline, the titlecompound was obtained as purple crystals.

¹H-NMR(DMSO-d₆)δ: 1.37(3H, t, J=7.4 Hz), 3.20(8H ,br.s), 4.05(2H, q,J=7.4 Hz), 6.71(1H, dt, J=8.6, 2.6 Hz), 6.89(1H, dd, J=8.6, 2.6 Hz),7.00(1H, dd, J=3.3, 2.6 Hz), 9.51(2H, br.s). IR(KBr): 3439, 2997, 2841,1624, 1521 cm⁻¹; MS(EI): 224(M⁺).

(4) Synthesis of N-(4-((4-(2-Ethoxy-4-fluorophenyl)piperazin-1-yl)methyl )phenylmethyl )acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2-ethoxy-4-fluorophenyl )piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as pale-browncrystals.

m.p.=108-109° C.; ¹H-NMR(CDCl₃)δ: 1.45(3H, t, J=6.6 Hz), 2.02(3H, s),2.62-2.64(4H, m), 3.04(4H, br.s), 3.56(2H, s), 4.02(2H, q, J=6.6 Hz),4.42(2H, d, J=5.3 Hz), 5.76(1H, br.s), 6.54-6.60(2H, m), 6.81(1H, dd,J=9.2, 5.9 Hz), 7.24(2H, d, J=7.9 Hz), 7.33(2H, d, J=7.9 Hz). IR(KBr):3423, 3261, 2929, 1637, 1602, 1560 cm⁻¹; MS(EI): 385(M⁺); Elementalanalysis: Calculated: C; 68.55, H; 7.32, N; 10.90; Found: C; 68.24, H;7.35, N; 10.70.

Example 42 Synthesis ofN-(4-((4-(4-Fluoro-2-isopropoxyphenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/4 Ethyl acetate

(1) Synthesis of 4-Fluoro-2-isopropoxynitrobenzene

By similar reaction and treatment to that in Example 41(1) usingisopropyl alcohol instead of ethanol, the title compound was obtained asan orange oil.

¹H-NMR(CDCl₃)δ: 1.42(6H, d, J=6.6 Hz), 4.63(1H, septet, J=6.6 Hz),6.65-6.79(2H, m), 7.45-7.90(1H, m). IR(KBr): 3091, 2983, 1620, 1589cm⁻¹; MS(EI): 199(M⁺).

(2) Synthesis of 4-Fluoro-2-isopropoxyaniline

By similar reaction and treatment to that in Example 40(2) using4-fluoro-2-isopropoxynitrobenzene instead of4-fluoro-2-methoxynitrobenzene, the title compound was obtained as ablack oil. ¹H-NMR(CDCl₃)δ: 1.35(6H, d, J=5.9 Hz), 3.47(2H, br.s),4.48(1H, septet, J=5.9 Hz), 6.44-6.65(3H, m). IR(KBr): 3460, 3373, 2980,1614, 1589 cm⁻¹; MS(EI): 169(M⁺);

(3) Synthesis of 1-(4-Fluoro-2-isopropoxyphenyl)piperazineDihydrochloride

By similar reaction and treatment to that in Example 40(3) using4-fluoro-2-isopropoxyaniline instead of 4-fluoro-2-methoxyaniline, thetitle compound was obtained as purple crystals.

¹H-NMR(DMSO-d₆)δ: 1.31(6H, d, J=5.9 Hz), 3.25(8H, br.s), 4.67(1H,septet, J=5.9 Hz), 6.71(1H, dt, J=8.6, 2.6 Hz), 7.93(1H, dd, J=11, 2.6Hz), 7.08(1H, dd, J=5.9, 2.6 Hz), 9.61(2H, br.s). IR(KBr): 3442, 2983,2925, 1626, 1522 cm⁻¹; MS(EI): 238(M⁺).

(4) Synthesis ofN-(4-((4-(4-Fluoro-2-isopropoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/4 Ethyl Acetate

By similar reaction and treatment to that in Example 1(5) using1-(4-fluoro-2-isopropoxyphenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as white crystals.

m.p.=211.5-213° C.; ¹H-NMR(DMSO-d₆)δ: 1.28(6H, d, J=5.9 Hz), 1.89(3H,s), 3.01-3.24(4H, m), 3.30-3.43(4H, m), 4.28(2H, d, J=5.9 Hz), 4.34(2H,s), 4.64(1H, septet, J=5.9 Hz), 6.67(1H, dd, J=7.9, 2.6 Hz),6.85-6.92(2H, m), 7.33(2H, d, J=7.9 Hz), 7.61(2H, d, J=7.9 Hz), 8.43(1H,t, J=5.9 Hz), 11.1(1H, br.s). IR(KBr): 3435, 3280, 2931, 1645, 1603,1541 cm⁻¹; MS(EI): 399(M⁺); Elemental analysis: Calculated: C; 63.36, H;7.17, N; 9.64; Found: C; 62.94, H; 7.26, N; 9.17.

Example 43 Synthesis ofN-(4-((4-(4-Fluoro-2-hydroxyphenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

(1) Synthesis of 1-Acetyl-4-(4-fluoro-2-nitrophenyl)piperazine

To a solution of 1-acetylpiperazine (20 g) in acetonitrile (50 ml) wereadded 2,5-difluoronitrobenzene (25 g) and potassium carbonate (22 g) andthe mixture was refluxed under heating at room temperature for 4.5 hr.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated to give a redoil. The oil was crystallized from ethyl acetate-isopropyl ether to givethe title compound (36 g) as a red solid.

¹H-NMR(CDCl₃)δ: 2.13(3H, s), 2.98-3.01(4H, m), 3.61(2H, dd, J=5.3, 4.6Hz), 3.77(2H, dd, J=5.3, 4.6 Hz), 7.16-7.31(2H, m), 7.53(1H, dd, J=7.9,3.3 Hz). IR(KBr): 3088, 2931, 1641, 1583 cm⁻¹; MS(EI): 267(M⁺).

(2) Synthesis of 1-Acetamido-4-(2-amino-4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 40(2) using1-acetamido-4-(4-fluoro-2-nitrophenyl)piperazine instead of4-fluoro-2-methoxynitrobenzene, the title compound was obtained as apale-brown solid.

¹H-NMR(CDCl₃)δ: 2.14(3H, s), 2.78-2.84(4H, m), 3.57-3.59(2H, m),3.73(1H, br.s), 4.16(1H, br.s), 6.31-6.61(2H, m), 6.85-7.58(1H, m).IR(KBr): 3429, 3319, 2960, 1626, 1506 cm⁻¹; MS(EI): 237(M⁺).

(3) Synthesis of 1-Acetyl-4-(4-fluoro-2-hydroxyphenyl)piperazine

To a solution of 1-acetyl-4-(2-amino-4-fluorophenyl)piperazine (25 g)and conc. sulfuric acid (42 ml) in water (210 ml) was added dropwise asolution of sodium nitrite (13 g) in water (46 ml) under ice-cooling.This reaction mixture was stirred at the same temperature for 4 hr andat room temperature for 6 hr. To the reaction mixture was added anaqueous sodium hydroxide solution to make it alkaline and acetylchloride was added dropwise. The mixture was stirred at the sametemperature for 30 min, passed through Celite and extracted with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated to give a blackoil. The oil was subjected to silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give a black solid.This solid was recrystallized from ethyl acetate-isopropyl ether to givethe title compound (0.66 g) as a pale-brown solid, m.p.=183-185° C.

¹H-NMR(CDCl₃)δ: 2.15(3H, s), 2.80-2.86(4H, m), 3.63(2H, dd, J=5.3, 4.6Hz), 3.78(2H, dd, J=5.3, 4.6 Hz), 6.57(1H, dd, J=8.6, 2.6 Hz), 6.69(1H,dd, J=8.9, 2.6 Hz), 7.05(1H, dd, J=8.6, 5.9 Hz), 7.16(1H, br.s).IR(KBr): 3290, 2916, 1630, 1601, 1502 cm⁻¹; MS(EI): 238(M⁺); Elementalanalysis: Calculated: C; 60.49, H; 6.35, N; 11.76; Found: C; 60.71, H;6.27, N; 11.80.

(4) Synthesis of 1-(4-Fluoro-2-hydroxyphenyl)piperazine Dihydrochloride

1-Acetyl-4-(4-fluoro-2-hydroxyphenyl)piperazine (0.64 g) was dissolvedin a 1.2N aqueous hydrochloric acid solution (16 ml) and refluxed underheating for 7 days. The reaction mixture was concentrated under reducedpressure to give a pale-brown solid. This solid was recrystallized frommethanol-ethyl acetate to give the title compound (0.65 g) as pale-browncrystals.

¹H-NMR(DMSO-d₆)δ: 3.29(8H, br.s), 5.33(1H, br.s), 6.62(1H, dt, J=8.6,2.6 Hz), 6.80(1H, dd, J=9.9, 2.6 Hz), 7.14-7.20(1H, m), 9.52(2H, br.s).IR(KBr): 3415, 3016, 2995, 1628, 1608 cm⁻¹; MS(EI): 169(M⁺).

(5) Synthesis ofN-(4-((4-(4-Fluoro-2-hydroxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

By similar reaction and treatment to that in Example 1(5) using1-(4-fluoro-2-hydroxyphenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as pale-red crystals.

m.p.=255-257° C.; ¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.04-3.37(9H, m),4.28(2H, d, J=5.3 Hz), 4.33(2H, s), 6.57(1H, dt, J=8.6, 2.6 Hz),6.69(1H, dd, J=11, 2.6 Hz), 6.91(1H, dd, J=8.6, 6.6 Hz), 7.33(2H, d,J=7.9 Hz), 7.60(2H, d, J=7.9 Hz), 8.45(1H, t, J=5.9 Hz), 11.2(1H, br.s).IR(KBr): 3246, 3089, 2885, 1618, 1597 cm⁻¹; MS(EI): 357(M⁺); Elementalanalysis: Calculated: C; 54.67, H; 6.19, N; 9.56; Found: C; 54.90, H;6.26, N; 9.47.

Example 44 Synthesis ofN-(4-((4-(2-Chloro-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Synthesis of 1-(2-Chloro-4-fluorophenyl)piperazine Dihydrochloride

By similar reaction and treatment to that in Example 40(3) using2-chloro-4-fluoroaniline instead of 4-fluoro-2-methoxyaniline, the titlecompound was obtained as pale-brown crystals, m.p.=203-204.5° C.

¹H-NMR(DMSO-d₆)δ: 3.19(8H, dd, J=12, 5.9 Hz), 7.17-7.29(2H, m),7.43-7.51(1H, m), 9.45(2H, br.s). IR(KBr): 3371, 2956, 2823, 1672, 1569cm⁻¹; MS(EI): 214(M⁺); Elemental analysis: Calculated: C; 47.83, H;5.22, N; 11.16; Found: C; 47.58, H; 5.25, N; 11.12.

(2) Synthesis ofN-(4-((4-(2-Chloro-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2-chloro-4-fluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as pale-red crystals.

m.p.=255-257° C.; ¹H-NMR(CDCl₃)δ: 2.03(3H, s), 2.62(4H, t, J=4.6 Hz),3.00(4H, t, J=4.6 Hz), 3.57(2H, s), 4.43(2H, d, J=5.3 Hz), 5.71(1H,br.s), 6.89-7.03(2H, m), 7.11(1H, dd, J=8.6, 2.6 Hz), 7.25(2H, d, J=7.9Hz), 7.34(2H, d, J=8.6 Hz). IR(KBr): 3277, 2949, 2821, 1633, 1556 cm⁻¹;MS(EI): 375(M⁺); Elemental analysis: Calculated: C; 63.91, H; 6.17, N;11.18; Found: C; 63.76, H; 6.26, N; 11.07.

Example 45 Synthesis ofN-(4-((4-(2-Bromo-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

(1) Synthesis of 1-(2-Bromo-4-fluorophenyl)piperazine dihydrochloride

By similar reaction and treatment to that in Example 40(3) using2-bromo-4-fluoroaniline instead of 4-fluoro-2-methoxyaniline, the titlecompound was obtained as pale-brown crystals, m.p.=208-210° C.

¹H-NMR(DMSO-d₆)δ: 3.17(8H, dd, J=8.6, 5.3 Hz), 7.26(2H, d, J=5.9 Hz),7.60(1H, d, J=8.6 Hz), 9.47(2H, br.s). IR(KBr): 2945, 2796, 2725, 1741,1591 cm⁻¹; MS(EI): 258(M⁺); Elemental analysis: Calculated: C; 40.63, H;4.43, N; 9.48; Found: C; 40.99, H; 4.54, N; 9.22.

(2) Synthesis of N-(4-((4-(2-Bromo-4-fluorophenyl)piperazin-1-yl )methyl)phenylmethyl)acetamide Dihydrochloride

By similar reaction and treatment to that in Example 1(5) using1-(2-bromo-4-fluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as pale-browncrystals.

m.p.=231-235° C.; ¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.13-3.38(8H, m),4.28(2H, d, J=5.9 Hz), 4.37(2H, d, J=4.6 Hz), 7.19-7.57(2H, m), 7.33(2H,d, J=7.9 Hz), 7.58-7.65(1H, m), 7.63(2H, d, J=7.9 Hz), 8.46(1H, t, J=5.9Hz), 11.5(1H, d, J=2.6 Hz). IR(KBr): 3228, 2979, 2958, 1753, 1668 cm⁻¹;MS(EI): 419(M⁺−1); Elemental analysis: Calculated: C; 48.70, H; 5.11, N;8.52; Found: C; 48.67, H; 5.19, N; 8.47.

Example 46 Synthesis ofN-(4-((4-(4-Fluoro-2-methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

(1) Synthesis of 1-(4-Fluoro-2-methylphenyl)piperazine Dihydrochloride

By similar reaction and treatment to that in Example 40(3) using4-fluoro-2-methylaniline instead of 4-fluoro-2-methoxyaniline, the titlecompound was obtained as pale-brown crystals, m.p.=258-260° C.

¹H-NMR(DMSO-d₆)δ: 2.27(3H, s), 3.45(8H, dd, J=5.1, 4.4 Hz), 3.19(4H,br.s), 6.97-7.10(3H, m), 9.64(2H, br.s). IR(KBr): 3007, 2925, 2792,1622, 1593 cm⁻¹; MS(EI): 194(M⁺); Elemental analysis: Calculated: C;49.45, H; 6.41, N; 10.49; Found: C; 49.23, H; 6.51, N; 10.51.

(2) Synthesis ofN-(4-((4-(4-Fluoro-2-methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

By similar reaction and treatment to that in Example 1(5) using1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as white crystals.

m.p.=115-117° C.; ¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.28(3H, s), 2.58(4H,br.s), 2.86(4H, t, J=4.6 Hz), 3.56(2H, s), 4.42(2H, d, J=5.9 Hz),5.76(1H, br.s), 6.78-6.99(3H, m), 7.24(2H, d, J=7.9 Hz), 7.32(2H, d,J=7.9 Hz). IR(KBr): 3278, 2949, 2821, 1651, 1552 cm⁻¹; MS(EI): 355(M⁺);Elemental analysis: Calculated: C; 70.96, H; 7.37, N; 11.82; Found: C;70.64, H; 7.44, N; 11.61.

Example 47 Synthesis ofN-(4-((4-(2,4,6-Trifluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

(1) Synthesis of 1-(2,4,6-Trifluorophenyl)piperazine Dihydrochloride

To a solution of 2,4,6-trifluoroaniline (4.4 g) anbis(2-chloroethyl)amine hydrochloride (6.4 g) in water (4.2 ml) wasadded dropwise a solution of sodium carbonate (3.8 g) in water (8.9 ml)over 40 min under reflux under heating and the mixture was furtherrefluxed under heating for 5.5 hr. To the reaction mixture was added anaqueous solution (8.9 ml) of sodium hydroxide (3.6 g) and the mixturewas further refluxed under heating for 2.5 hr. The reaction mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated to give a dark brown oil. The oil was subjected to silicagel column chromatography (developing solvent; chloroform:methanol=9:1)to give the title compound (0.61 g) as a pale-brown solid.

¹H-NMR(DMSO-d₆)δ: 2.86(2H, br.s), 3.03(2H, br.s), 4.07(4H, br.s),7.13(2H, t, J=9.5 Hz). IR(KBr): 3205, 2954, 2846, 1633, 1594 cm⁻¹;MS(EI): 216(M⁺).

(2) Synthesis ofN-(4-((4-(2,4,6-Trifluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride

By similar reaction and treatment to that in Example 1(5) using1-(2,4,6-trifluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as white crystals.

m.p.=235-240° C. (decomposition); ¹H-NMR(DMSO-d₆)δ: 1.89(3H, s),3.09-3.31(6H, m), 3.58(2H, t, J=12 Hz), 4.28(2H, d, J=5.9 Hz), 4.34(2H,d, J=4.6 Hz), 7.19(2H, t, J=9.2 Hz), 7.32(2H, d, J=7.9 Hz), 7.62(2H, d,J=7.9 Hz), 8.47(1H, t, J=5.9 Hz), 11.5(1H, br.s). IR(KBr): 3259, 2926,2856, 1635, 1598 cm⁻¹; Elemental analysis: Calculated: C; 53.34, H;5.37, N; 9.33; Found: C; 53.35, H; 5.59, N; 9.34.

Example 48 Synthesis ofN-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) Synthesis of 4-Chloromethylacetophenone

To a solution of 4-chloromethylbenzoyl chloride (40 g) andtris(acetylacetonato) iron (0.75 g) in tetrahydrofuran (400 ml) wasadded dropwise methylmagnesium bromide (3M, tetrahydrofuran solution)(70ml) under ice-cooling and the mixture was stirred at 0° C. for 2 hr. Thereaction mixture was poured into water and passed through Celite. TheCelite was washed with ethyl acetate and the filtrate was combined. Themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated to give a black red oil. The oil wassubjected to silica gel column chromatography (developing solvent;hexane:ethyl acetate=9:1, then ethyl acetate) to give the title compound(19 g) as a pale-brown oil.

¹H-NMR(CDCl₃)δ: 2.60(3H, s), 4.61(2H, s), 7.48(2H, d, J=7.9 Hz),7.95(2H, d, J=7.9 Hz). IR(KBr): 3005, 2964, 1683, 1609, 1574 cm⁻¹;MS(EI): 168(M⁺);

(2) Synthesis of 1-(4-Chloromethylphenyl)ethanol

To a solution of sodium borohydride (4.9 g) in methanol (70 ml) wasadded dropwise a solution of 4-chloromethylacetophenone (22 g) inmethanol(60 ml) under ice-cooling, and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated to give a pale-brown substance. The substance was subjectedto silica gel column chromatography (developing solvent; hexane:ethylacetate=2:1) to give the title compound (17 g) as a colorless oil.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=6.6 Hz), 4.59(2H, s), 4.91(1H, q, J=6.6Hz), 7.73(4H, s). IR(KBr): 3360, 2974, 1513, 1445 cm⁻¹; MS(EI): 170(M⁺).

(3) Synthesis of N-(1-(4-Chloromethylphenyl)ethyl)acetamide

To a solution of 1-(4-chloromethylphenyl)ethanol (17 g) in acetonitrile(102 ml) was added dropwise conc. sulfuric acid (5.7 ml) underice-cooling. The mixture was stirred at 0° C. for 3.5 hr and leftstanding overnight. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with an aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated to give a whitesolid. This solid was recrystallized from ethyl acetate-isopropyl etherto give the title compound (17 g) as white crystals.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 1.98(3H, s), 4.57(2H, s),5.12(1H, dq, J=7.3, 6.6 Hz), 5.77(1H, br.s), 7.30(2H, d, J=7.9 Hz),7.36(2H, d, J=7.9 Hz). IR(KBr): 3267, 3061, 2978, 1631, 1540 cm⁻¹;MS(EI): 211(M⁺).

(4) Synthesis ofN-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluorophenyl)piperazine instead of phenylpiperazine andN-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals, m.p.=101-103° C.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=6.6 Hz), 1.99(3H, s), 2.60(4H, dd, J=5.3,4.6 Hz), 3.11(4H, dd, J=5.3, 4.6 Hz), 3.55(2H, s), 5.13(1H, dq, J=7.3,6.6 Hz), 5.65(1H, d, J=7.3 Hz), 6.83-6.98(4H, m), 7.27(2H, d, J=7.9 Hz),7.32(2H, d, J=7.9 Hz). IR(KBr): 3355, 2943, 2816, 1645, 1507 cm⁻¹;MS(EI): 355(M⁺); Elemental analysis: Calculated: C; 70.96, H; 7.37, N;11.82; Found: C; 70.88, H; 7.51, N; 11.79.

Example 49 Synthesis ofN-(1-(4-((4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2,4-difluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide insteadof N-(4-chloromethylphenylmethyl)acetamide, the title compound wasobtained as white crystals, m.p.=109-111° C.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=6.6 Hz), 1.99(3H, s), 2.62(4H, t, J=4.6Hz), 3.04(4H, t, J=4.6 Hz), 3.56(2H, s), 5.13(1H, quintet, J=7.3 Hz),5.65(1H, d, J=7.9 Hz), 6.74-6.94(3H, m), 7.27(2H, d, J=7.9 Hz), 7.32(2H,d, J=7.9 Hz). IR(KBr): 3351, 2946, 2811, 1644, 1505 cm⁻¹; MS(EI):373(M⁺); Elemental analysis: Calculated: C; 67.54, H; 6.75, N; 11.25;Found: C; 67.38, H; 6.80, N; 11.21.

Example 50 Synthesis ofN-(1-Methyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) Synthesis of 1-(4-Chloromethylphenyl)-1-methylethanol

To a solution of 4-chloromethylbenzoyl chloride (40 g) intetrahydrofuran (400 ml) was added dropwise methylmagnesium bromide (3M,tetrahydrofuran solution) (70 ml) under ice-cooling and the mixture wasstirred at 0° C. for 4 hr. The reaction mixture was poured into anaqueous ammonium chloride solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate and the solvent was evaporated to give a yellow oil.The oil was subjected to silica gel column chromatography (developingsolvent; hexane:ethyl acetate=9:1) to give an orange oil. The oil wassubjected to silica gel column chromatography (developing solvent;hexane:ethyl acetate=4:1) to give the title compound (10 g) as apale-brown oil, m.p.=101-103° C.

¹H-NMR(CDCl₃)δ: 1.58(6H, s), 4.58(2H, s), 7.36(2H, d, J=8.6 Hz),7.48(2H, d, J=8.6 Hz). IR(KBr): 3407, 2976, 2932, 1677, 1610 cm⁻¹;MS(EI): 184(M⁺).

(2) Synthesis of N-(1-(4-Chloromethylphenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 48(3) using1-(4-chloromethylphenyl)-1-methylethanol instead of1-(4-chloromethylphenyl)ethanol, the title compound was obtained as apale-brown substance, m.p.=101-103° C.

¹H-NMR(CDCl₃)δ: 1.66(6H, s), 1.95(3H, s), 4.56(2H, s), 5.82(1H, br.s),7.33(2H, d, J=8.6 Hz), 7.37(2H, d, J=8.6 Hz). IR(KBr): 3317, 3074, 2974,1658, 1553 cm⁻¹; MS(EI): 225(M⁺).

(3) Synthesis ofN-(1-Methyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals, m.p.=110-111° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.60(4H, dd, J=5.3, 4.6 Hz),3.19(4H, dd, J=5.3, 4.6 Hz), 3.54(2H, s), 5.70(1H, br.s), 6.84(1H, t,J=7.3 Hz), 6.91(2H, d, J=7.9 Hz), 7.25(2H, ddd, J=5.3, 4.6, 2.0 Hz),7.30(2H, d, J=8.6 Hz), 7.35(2H, d, J=8.6 Hz). IR(KBr): 3325, 2923, 2810,1659, 1601 cm⁻¹; MS(EI): 351(M⁺); Elemental analysis: Calculated: C;75.18, H; 8.32, N; 11.96; Found: C; 75.10, H; 8.28, N; 11.87.

Example 51 Synthesis ofN-(1-Methyl-1-(4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluorophenyl)piperazine instead of phenylpiperazine andN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas pale-brown crystals, m.p.=104.5-106° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.60(4H, dd, J=5.3, 4.6 Hz),3.11(4H, dd, J=5.3, 4.6 Hz), 3.54(2H, s), 5.70(1H, br.s), 6.83-7.02(4H,m), 7.29(2H, d, J=8.6 Hz), 7.32(2H, d, J=8.6 Hz). IR(KBr): 3323, 3002,2811, 1658, 1549 cm⁻¹; MS(EI): 369(M⁺); Elemental analysis: Calculated:C; 71.52, H; 7.64, N; 11.37; Found: C; 71.43, H; 7.65, N; 11.25.

Example 52 Synthesis ofN-(1-Methyl-1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamideHydrochloride 1/4 Hydrate

By similar reaction and treatment to that in Example 1(5) using1-(2,4-difluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine and N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamideinstead of N-(4-chloromethylphenylmethyl)acetamide, the title compoundwas obtained as pale-brown crystals.

m.p.=240.5-242° C.; ¹H-NMR(DMSO-d₆)δ: 1.54(6H, s), 1.85(3H, s),3.21-3.41(8H, m), 4.32(2H, d, J=4.0 Hz), 6.80-7.28(3H, m), 7.38(2H, d,J=7.9 Hz), 7.59(2H, d, J=7.9 Hz), 8.17(1H, s), 11.6(1H, br.s). IR(KBr):3287, 2976, 2468, 1645, 1596 cm⁻¹; MS(EI): 387(M⁺); Elemental analysis:Calculated: C; 61.68, H; 6.71, N; 9.81; Found: C; 61.42, H; 6.62, N;9.65.

Example 53 Synthesis ofN-(1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide

(1) Synthesis of (4-Chloromethylphenyl)ethyl Ketone

By similar reaction and treatment to that in Example 48(1) usingethylmagnesium bromide (3M, ether solution) instead of methylmagnesiumbromide (3M, tetrahydrofuran solution), the title compound was obtainedas a pale-yellow substance. ¹H-NMR(CDCl₃)δ: 1.23(3H, t, J=7.3 Hz),3.00(2H, q, J=7.3 Hz), 4.61(2H, s), 7.48(2H, d, J=8.6 Hz), 7.96(2H, d,J=8.6 Hz). IR(KBr): 2980, 2939, 1716, 1687, 1574 cm⁻¹; MS(EI): 182(M⁺).

(2) Synthesis of 1-(4-Chloromethylphenyl)propanol

By similar reaction and treatment to that in Example 48(2) using(4-chloromethylphenyl)ethyl ketone instead of4-chloromethylacetophenone, the title compound was obtained as acolorless oil.

¹H-NMR(CDCl₃)δ: 0.92(3H, t, J=7.3 Hz), 1.65-1.89(2H, m), 4.58(2H, s),4.60(1H, t, J=6.6 Hz), 7.33(2H, d, J=8.6 Hz), 7.37(2H, d, J=8.6 Hz).IR(KBr): 3371, 2964, 2933, 1614, 1514 cm⁻¹; MS(EI): 184(M⁺).

(3) Synthesis of N-(1-(4-Chloromethylphenyl)propyl)acetamide

By similar reaction and treatment to that in Example 48(3) using1-(4-chloromethylphenyl)propanol instead of1-(4-chloromethylphenyl)ethanol, the title compound was obtained as awhite substance.

¹H-NMR(CDCl₃)δ: 0.89(3H, t, J=7.3 Hz), 1.70-1.93(2H, m), 1.98(3H, s),4.57(2H, s), 4.88(1H, q, J=7.9 Hz), 5.68(1H, d, J=7.3 Hz), 7.27(2H, d,J=7.9 Hz), 7.35(2H, d, J=7.9 Hz). IR(KBr): 3299, 2964, 2933, 1639, 1553cm⁻¹; MS(EI): 225(M⁺).

(4) Synthesis ofN-(1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)propyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas pale-brown crystals, m.p.=109-110.5° C.

¹H-NMR(CDCl₃)δ: 0.89(3H, dd, J=7.9, 7.3 Hz), 1.74-1.91(2H, m), 1.99(3H,s), 2.60(4H, dd, J=5.3, 4.6 Hz), 3.20(4H, dd, J=5.3, 4.6 Hz), 3.55(2H,s), 4.88(1H, dt, J=7.9, 7.3 Hz), 5.65(1H, d, J=7.9 Hz), 6.84(1H, t,J=7.3 Hz), 6.92(2H, d, J=7.9 Hz), 7.24(2H, d, J=7.9 Hz), 7.31(2H, d,J=7.9 Hz). IR(KBr): 3310, 2924, 2812, 1649, 1540 cm⁻¹; MS(EI): 351(M⁺);Elemental analysis: Calculated: C; 75.18, H; 8.32, N; 11.96; Found: C;75.00, H; 8.41, N; 11.86.

Example 54 Synthesis ofN-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)propyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluorophenyl)piperazine instead of phenylpiperazine andN-(1-(4-chloromethylphenyl)propyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas pale-brown crystals, m.p.=113-114° C.

¹H-NMR(CDCl₃)δ: 0.89(3H, dd, J=7.9, 7.3 Hz), 1.74-1.90(2H, m), 1.99(3H,s), 2.60(4H, dd, J=5.3, 4.6 Hz), 3.11(4H, dd, J=5.3, 4.6 Hz), 3.54(2H,s), 4.88(1H, dt, J=7.9, 7.3 Hz), 5.66(1H, d, J=7.9 Hz), 6.83-6.99(4H,m), 7.23(2H, d, J=7.9 Hz), 7.32(2H, d, J=7.9 Hz). IR(KBr): 3308, 2960,2811, 1647, 1510 cm⁻¹; MS(EI): 369(M⁺); Elemental analysis: Calculated:C; 71.52, H; 7.64, N; 11.37; Found: C; 71.48, H; 7.75, N; 11.35.

Example 55 Synthesis ofN-(1-(4-((4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)phenyl)propyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2,4-difluorophenyl)piperazine instead of phenylpiperazine andN-(1-(4-chloromethylphenyl)propyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas pale-brown crystals, m.p.=137-138° C.

¹H-NMR(CDCl₃)δ: 0.89(3H, t, J=7.3 Hz), 1.74-1.90(2H, m), 1.99(3H, s),2.62(4H, t, J=4.6 Hz), 3.04(4H, t, J=4.6 Hz), 3.55(2H, s), 4.88(1H, dt,J=7.8, 7.3 Hz), 5.69(1H, d, J=7.8 Hz), 6.74-6.94(3H, m), 7.23(2H, d,J=7.9 Hz), 7.31(2H, d, J=7.9 Hz). IR(KBr): 3316, 2946, 2828, 1647, 1508cm⁻¹; MS(EI): 387(M⁺); Elemental analysis: Calculated: C; 68.20, H;7.02, N; 10.84; Found: C; 68.26, H; 7.08, N; 10.79.

Example 56 Synthesis ofN-(1-Ethyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide

(1) Synthesis of 1-(4-Chloromethylphenyl)-1-ethylpropanol

By similar reaction and treatment to that in Example 50(1) usingethylmagnesium bromide (3M, ether solution) instead of methylmagnesiumbromide (3M, tetrahydrofuran solution), the title compound was obtainedas a brown oil.

¹H-NMR(CDCl₃)δ: 0.76(6H, dd, J=7.9, 7.3 Hz), 1.73-1.93(4H, m), 4.59(2H,s), 7.36(4H, s). IR(KBr): 3473, 2968, 2937, 1612, 1511 cm⁻¹; MS(EI):183(M+−Et).

(2) Synthesis of N-(1-(4-Chloromethylphenyl)-1-ethylpropyl)acetamide

By similar reaction and treatment to that in Example 48(3) using1-(4-chloromethylphenyl)-1-ethylpropanol instead of1-(4-chloromethylphenyl)ethanol, the title compound was obtained as apale-brown oil.

¹H-NMR(CDCl₃)δ: 0.73(6H, dd, J=7.9, 7.3 Hz), 1.91-2.21(4H, m), 2.01(3H,s), 4.57(2H, s), 5.54(1H, s), 7.29(2H, d, J=8.6 Hz), 7.35(2H, d, J=8.6Hz). IR(KBr): 3288, 2979, 2966, 1644, 1551 cm⁻¹; MS(EI): 254(M++1).

(3) Synthesis ofN-(1-Ethyl-1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-ethylpropyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals, m.p.=139-140° C.

¹H-NMR(CDCl₃)δ: 0.73(6H, dd, J=7.9, 7.3 Hz), 1.93-2.22(4H, m), 2.03(3H,s), 2.61(4H, dd, J=5.3, 4.6 Hz), 3.20(4H, dd, J=5.3, 4.6 Hz), 3.54(2H,s), 5.51(1H, br.s), 6.84(1H, t, J=7.3 Hz), 6.92(2H, d, J=7.9 Hz),7.21-7.33(6H, m). IR(KBr): 3269, 2973, 2827, 1648, 1602 cm⁻¹; MS(EI):379(M⁺); Elemental analysis: Calculated: C; 75.95, H; 8.76, N; 11.07;Found: C; 75.96, H; 8.96, N; 10.92.

Example 57 Synthesis ofN-(1-(4-((4-Phenylpiperazin-1-yl)methyl)-phenyl)cyclopropyl)acetamide

(1) Synthesis of Methyl 1-Phenylcyclopropanecarboxylate

To a solution of 1-phenylcyclopropanecarboxylic acid (9.8 g) in methanol(121 ml) was added conc. sulfuric acid (0.1 ml) and the mixture wasrefluxed under heating for 8 hr. The reaction mixture was neutralized byadding an aqueous potassium carbonate solution and concentrated underreduced pressure. The concentrate was extracted with ethyl acetate. Theextract was washed with an aqueous sodium hydrogencarbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated to give the title compound (8.5 g) as a colorless oil.

¹H-NMR(CDCl₃)δ: 1.20(2H, dd, J=6.6, 3.7 Hz), 1.61(2H, dd, J=6.6, 3.7Hz), 3.62(3H, s), 7.24-7.36(5H, m). IR(KBr): 3059, 2953, 1724, 1603cm⁻¹; MS(EI): 176(M⁺).

(2) Synthesis of Methyl 1-(4-Chloromethylphenyl)cyclopropanecarboxylate

To a solution of methyl 1-phenylcyclopropanecarboxylate (8.5 g) inmethylene chloride (70 ml) was added titanium tetrachloride (8.0 ml)under ice-cooling. To this solution was added dropwise a solution ofmethoxymethyl chloride (5.5 ml) in methylene chloride (30 ml) underice-cooling. The mixture was stirred at room temperature for 5 hr andleft standing overnight. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with an aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated to give apale-brown oil. The oil was subjected to silica gel columnchromatography (developing solvent; hexane:ethyl acetate=4:1) to givethe title compound (7.9 g) as a colorless oil.

¹H-NMR(CDCl₃)δ: 1.19-1.21(2H, m), 1.58-1.64(2H, m), 3.62(3H, s),4.57(2H, s), 7.33(4H, s). IR(KBr): 3016, 2954, 1717, 1604 cm⁻¹; MS(EI):224(M⁺).

(3) Synthesis of Methyl1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate

By similar reaction and treatment to that in Example 1(5) using methyl1-(4-chloromethylphenyl)cyclopropanecarboxylate instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas a pale-yellow solid.

¹H-NMR(CDCl₃)δ: 1.19(2H, dt, J=4.0, 3.3 Hz), 1.60(2H, dt, J=4.0, 3.3Hz), 2.61(4H, dd, J=5.3, 4.6 Hz), 3.20(4H, dd, J=5.3, 4.6 Hz), 3.55(2H,s), 3.62(3H, s), 6.84(1H, t, J=7.3 Hz), 6.91(2H, d, J=8.6 Hz),7.25-7.32(6H, m). IR(KBr): 2934, 2923, 1713, 1601 cm⁻¹; MS(EI): 350(M⁺).

(4) Synthesis of(4-((4-Phenylpiperazin-1-yl)methyl)phenylcyclopropanecarboxylic Acid

Methyl1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)-cyclopropanecarboxylate(1.9 g) was dissolved in a mixed solution of methanol (50 ml) andtetrahydrofuran (10 ml) and lithium hydroxide monohydrate (0.46 g) wasadded. The mixture was refluxed under heating for 4 hr. The reactionmixture was neutralized with hydrochloric acid, and concentrated underreduced pressure and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated to give the title compound (1.2 g) as apale-brown solid.

¹H-NMR(CDCl₃)δ: 1.07(2H, t, J=3.3 Hz), 1.40(2H, t, J=3.3 Hz), 2.50(4H,t, J=4.6 Hz), 3.11(4H, t, J=4.6 Hz), 3.48(2H, s), 3.73(1H, br.s),6.76(1H, t, J=7.3 Hz), 6.91(2H, d, J=8.6 Hz), 7.16-7.29(6H, m). IR(KBr):2934, 2822, 1697, 1600 cm⁻¹; MS(EI): 336(M⁺).

(5) Synthesis ofN-(1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

To a solution of(4-((4-phenylpiperazin-1-yl)methyl)-phenylcyclopropanecarboxylic acid(1.0 g) and triethylamine (0.42 ml) in tetrahydrofuran (70 ml) was addedethyl chlorocarbonate (0.29 ml) under ice-cooling and the mixture wasstirred at 0° C. for 1 hr and 20 min. To this solution was added asolution of sodium azide (0.2 g) in water (3 ml) under ice-cooling, andthe mixture was stirred for 30 min and left standing overnight. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give a brown oil. Theoil was dissolved in benzene (20 ml) and refluxed under heating for 40min. The reaction mixture was ice-cooled and methylmagnesium bromide(3M, tetrahydrofuran solution) (0.93 ml) was added dropwise. The mixturewas stirred at room temperature for 1 hr. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated to give a colorless oil. The oil wassubjected to silica gel column chromatography (developing solvent; ethylacetate:methanol=20:1) to give a white solid. This solid wasrecrystallized from ethyl acetate-isopropyl ether to give the titlecompound (0.52 g) as white crystals, m.p.=129-139.5° C.

¹H-NMR(CDCl₃)δ: 1.26(4H, br.s), 1.99(3H, s), 2.58(4H, dd, J=5.3, 4.6Hz), 3.18(4H, dd, J=5.3, 4.6 Hz), 3.51(2H, s), 6.15(1H, br.s), 6.84(1H,t, J=7.3 Hz), 6.91(2H, d, J=7.9 Hz), 7.09-7.32(6H, m). IR(KBr): 3308,2824, 1658, 1603, 1517 cm⁻¹; MS(EI): 349(M⁺); Elemental analysis:Calculated: C; 75.61, H; 7.99, N; 12.05; Found: C; 75.36, H; 7.79, N;11.85.

Example 58 Synthesis ofN-(1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamideDihydrochloride 1/4 Hydrate

(1) N-(1-Phenylethyl)acetamide

To a solution of 1-phenylethylamine (10.45 g) and triethylamine (14.4ml) in dichloromethane (100 ml) was added dropwise acetic anhydride (9.0ml) at room temperature. The mixture was stirred at room temperature for5 hr. The reaction mixture was poured into ice water (200 ml) andextracted with chloroform. The organic layer was dried over anhydroussodium sulfate and the solvent was evaporated. The obtained residue wasleft standing at room temperature for 3 hr. The obtained crude crystalswere washed several times with hexane to give the title compound (14.0g) as white crystals.

¹H-NMR(CDCl₃)δ: 1.46(3H, d, J=6.6 Hz), 1.95(3H, s), 5.10(1H, dt, J=5.4,5.4 Hz), 6.10(1H, brs), 7.30(5H, m). IR(KBr): 3282, 3062, 2979, 1645,1552 cm⁻¹; MS(EI): 163(M⁺).

(2) N-(1-(4-Formylphenyl)ethyl)acetamide

To a solution of N-(1-phenylethyl)acetamide (5.0 g) in dichloromethane(100 ml) was added dropwise titanium tetrachloride (16.7 ml) at below 5°C. over 30 min. Thereto was added dropwise a solution of dichloromethylmethyl ether (14.1 ml) in dichloromethane (30 ml) solution at below 5°C. over 30 min. The mixture was stirred at 25° C. for 3 hr, at roomtemperature for 12 hr, and then at 25° C. for 3 hr, and poured into icewater (800 ml) and extracted with ethyl acetate. The extract was washedsuccessively with a saturated sodium hydrogencarbonate solution (500 ml)and saturated brine (500 ml), and dried over anhydrous sodium sulfate.The solvent was evaporated and the obtained residue was purified bysilica gel column chromatography (elution solvent; hexane:ethylacetate=1:3) to give the title compound (0.35 g) as a colorless oil.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=7.3 Hz), 2.01(3H, s), 5.17(1H, dt, J=7.1,7.1 Hz), 6.04(1H, brs), 7.47(2H, d, J=7.9 Hz), 7.84(2H, d, J=8.6 Hz),9.98(1H, s); MS(EI): 191(M⁺).

(3) N-(1-(4-((4-Phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamideDihydrochloride 1/4 Hydrate

A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g) and sodiumborohydride (63 mg) in ethanol (10 ml) was stirred at room temperaturefor 1 hr. Thereto was added 2N hydrochloric acid (1 ml) to stop thereaction, and the reaction mixture was poured into ice water (100 ml)and extracted with ethyl acetate. The extract was washed successivelywith saturated sodium hydrogencarbonate solution (500 ml) and saturatedbrine (500 ml) and dried over anhydrous sodium sulfate. The solvent wasevaporated and the obtained residue was purified by silica gel columnchromatography (elution solvent; hexane:ethyl acetate=2:5, later 1:4) togive N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) as a colorlessoil. A solution of the obtainedN-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionylchloride (0.050 ml) in chloroform (5 ml) was stirred at 60° C. for 1 hr.This was diluted with ethyl acetate (100 ml) and poured into a saturatedsodium hydrogencarbonate solution (100 ml) to separate the organiclayer. The aqueous layer was extracted with ethyl acetate (100 ml) andcombined with the organic layer obtained earlier. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the obtained residue was purified by silicagel column chromatography (elution solvent; ethyl acetate alone) to giveN-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow crystals.

By similar reaction and treatment to that in Example 1(5) using theobtained N-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, and treatment with a solutionof 1M hydrochloric acid in ether, the title compound (40 mg) wasobtained as white crystals, m.p.=196-200° C.

¹H-NMR(DMSO-d₆)δ: 1.34(3H, s), 1.85(3H, s), 3.20(4H, m), 3.33(2H, m),3.78(2H, m), 4.34(2H, s), 6.86(1H, t, J=7.3 Hz), 6.97(2H, d, J=8.6 Hz),7.26(1H, t, J=7.9 Hz), 7.38(2H, d, J=8.6 Hz), 7.61(2H, d, J=8.6 Hz),8.40(2H, d, J=7.9 Hz), 11.41(1H, brs). IR(KBr): 3437, 3244, 3055, 2987,1639 cm⁻¹; MS(EI): 337(M⁺); Elemental analysis: Calculated: C; 60.79, H;7.17, N; 10.13; Found: C; 60.69, H; 7.27, N; 9.84.

Example 59 Synthesis ofN-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

(1) (4-Azidomethylphenyl)methyl Ketone

A solution of 4-chloromethylacetophenone (8.8 g) obtained in Example48(1) and sodium azide in dimethylformamide (52 ml) was stirred at 50°C. for 3 hr. The reaction mixture was poured into ice water (200 ml) andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated and the obtained residue was purified by silica gel columnchromatography (elution solvent; hexane:ethyl acetate=4:1) to give thetitle compound (8.61 g) as a yellow oil.

¹H-NMR(CDCl₃)δ: 2.61(3H, s), 4.42(2H, s), 7.42(2H, d, J=7.9 Hz),7.97(2H, d, J=8.6 Hz). IR(neat): 2102, 1684, 1608 cm⁻¹.

(2) N-(4-(1-Hydroxyethyl)phenylmethyl)acetamide

To a suspension of aluminum lithium hydride (5.31 g) in tetrahydrofuran(500 ml) was added dropwise a solution of (4-azidomethylphenyl) methylketone (8.18 g) in tetrahydrofuran (100 ml) at below 5° C. over 30 min.The mixture was stirred at 30° C. for 2 hr. A saturated aqueous sodiumsulfate solution (30 ml) was added and the mixture was stirred for 1 hr.The insoluble matter was filtered off and the solvent was evaporated.The obtained residue was dissolved in ethyl acetate (100 ml), 2N aqueoussodium hydroxide solution (30 ml) and water (70 ml). Thereto was addeddropwise acetic anhydride (4.8 ml) with vigorous agitation at 10-15° C.over 10 min. The mixture was stirred at room temperature for 1 hr. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate and combined with the organic layer. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the obtained residue was purified by silicagel column chromatography (elution solvent; methanol:chloroform=3:97,later 5:95) to give the title compound (5.37 g) as a rather brown oil.

¹H-NMR(CDCl₃)δ: 1.46(3H, d, J=6.6 Hz), 1.98(3H, s), 2.21(1H, brs),4.36(2H, d, J=5.3 Hz), 4.87(1H, q, J=6.4 Hz), 6.88(1H, brs), 7.22(2H, d,J=8.6 Hz), 7.32(2H, d, J=7.9 Hz). IR(neat): 3296, 2972, 2821, 1653, 1556cm⁻¹; MS(EI): 193(M⁺).

(3) N-(4-(1-Chloroethyl)phenylmethyl)acetamide

To a solution of N-(4-(1-hydroxyethyl)phenylmethyl)acetamide (5.26 g) inchloroform (40 ml) was added dropwise a solution of thionyl chloride(2.1 ml) in chloroform (10 ml) at below 5° C. over 20 min. The mixturewas stirred at 30° C. for 1 hr. The mixture was poured into a saturatedsodium hydrogencarbonate solution and extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated. The obtained residue was purified by silica gel columnchromatography (elution solvent; methanol:chloroform=4:96) to give thetitle compound (4.08 g) as white crystals.

m.p.=58-62° C. ¹H-NMR(CDCl₃)δ: 1.83(3H, d, J=6.6 Hz), 1.99(3H, s),4.39(2H, d, J=5.9 Hz), 5.07(1H, q, J=6.8 Hz), 6.12(1H, brs), 7.25(2H, d,J=7.9 Hz), 7.37(2H, d, J=7.9 Hz). IR(KBr): 3286, 1649, 1547 cm⁻¹;MS(EI): 211((M+1)+); Elemental analysis: Calculated: C; 62.41, H; 6.67,N; 6.62; Found: C; 62.68, H; 6.81, N; 6.59.

(4)N-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazineand N-(4-(1-chloroethyl)phenylmethyl)acetamide instead ofN-(4-chloromethylphenylmethyl) acetamide, the title compound wasobtained as white crystals, m.p.=128-130° C.

¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.87(3H, s), 2.37-2.77(4H, m),3.03(4H, t, J=5.0 Hz), 3.39(1H, q, J=7.3 Hz), 4.23(2H, d, J=5.3 Hz),6.86-7.05(4H, m), 7.21(2H, d, J=7.9 Hz), 7.27(2H, d, J=8.6 Hz), 8.30(1H,t, J=5.6 Hz). IR(KBr): 3323, 2818, 1651, 1535, 1510 cm⁻¹; MS(EI):355(M⁺); Elemental analysis: Calculated: C; 70.96, H; 7.37, N; 11.82;Found: C; 71.09, H; 7.41, N; 11.74.

Example 60 Synthesis ofN-(1-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

(1) N-(1-(4-(1-Hydroxyethyl)phenyl)-1-methylethyl)acetamide

To a solution of N-(1-(4-acetylphenyl)-1-methylethyl)acetamide (50.0 g)in methanol (400 ml) was added dropwise sodium borohydride (4.3 g) atbelow 5° C. over 30 min. The mixture was stirred at room temperature for2 hr and 2N hydrochloric acid (60 ml) was added. The mixture was treatedby a conventional method and the obtained crude crystals wererecrystallized from ethanol to give the title compound (42.17 g) aswhite crystals.

m.p.=146-149° C.; ¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.52(6H, s),1.81(3H, s), 4.67(1H, q, J=6.4 Hz), 7.23(4H, s), 7.99(1H, s). MS(EI):221(M⁺);

(2) N-(1-(4-(1-Chloroethyl)phenyl)-1-methylethyl)acetamide

N-(1-(4-(1-Hydroxyethyl)phenyl)-1-methylethyl)acetamide was chlorinatedin the same manner as in Example 59(3) to give the title compound aswhite crystals.

¹H-NMR(CDCl₃)δ: 1.67(6H, s), 1.83(3H, d, J=6.6 Hz), 1.95(3H, s),5.07(1H, q, J=6.8 Hz), 5.88(1H, brs), 7.39(4H, s). MS(EI): 239(M⁺).

(3)N-(1-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazineand N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas white crystals.

m.p.=156-157° C. ¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.53(6H, s),1.83(3H, s), 2.40-2.56(4H, m), 3.03(4H, t, J=4.6 Hz), 3.38(1H, m),6.87-7.05(4H, m), 7.21(2H, d, J=8.6 Hz), 7.26(2H, d, J=8.6 Hz), 7.98(1H,s) IR(KBr): 3327, 2818, 1659, 1547, 1512 cm⁻¹; MS(EI): 383(M⁺);Elemental analysis: Calculated: C; 72.03, H; 7.88, N; 10.96; Found: C;71.90, H; 7.99, N; 10.76.

Example 61 Synthesis ofN-(1-(4-(1-(4-(2,4-Difluorophenyl)-piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2,4-difluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine andN-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide obtained inExample 60(2) instead of N-(4-chloromethylphenylmethyl) acetamide, thetitle compound was obtained as a white amorphous solid.

¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.53(6H, s), 1.83(3H, s),2.42-2.57(4H, m), 2.93(4H, m), 3.39(1H, q, J=6.6 Hz), 6.92-7.18(3H, m),7.21(2H, d, J=8.6 Hz), 7.27(2H, d, J=8.6 Hz), 7.99(1H, s). IR(KBr):3331, 2975, 2821, 1659, 1547, 1508 cm⁻¹; MS(EI): 401(M⁺); Elementalanalysis: Calculated: C; 68.80, H; 7.28, N; 10.47; Found: C; 68.76, H;7.38, N; 10.28.

Example 62 Synthesis ofN-(1-(4-(1-(4-Phenylpiperazin-1-yl)ethyl)-phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide obtained inExample 103(2) instead of N-(4-chloromethylphenylmethyl) acetamide, thetitle compound was obtained as white crystals.

m.p.=169-171° C.; ¹H-NMR(DMSO-d₆)δ: 1.31(3H, d, J=7.3 Hz), 1.53(6H, s),1.83(3H, s), 2.38-2.58(4H, m), 3.09(4H, t, J=4.6 Hz), 3.38(1H, q, J=6.6Hz), 6.75(1H, t, J=7.3 Hz), 6.88(2H, d, J=7.9 Hz), 7.18(2H, t, J=7.3Hz), 7.22(2H, d, J=8.6 Hz), 7.27(2H, d, J=8.6 Hz), 7.98(1H, s); IR(KBr):3286, 2974, 2823, 1655, 1603 cm⁻¹; MS(EI): 365(M⁺); Elemental analysis:Calculated: C; 75.58, H; 8.55, N; 11.50; Found: C; 75.28, H; 8.60, N;11.41.

Example 63 Synthesis ofN-(4-(1-(4-(2,4-Difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

By similar reaction and treatment to that in the above-mentionedExamples, the title compound was obtained.

m.p.=96-97° C.

Example 64 Synthesis ofN-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)phenylmethyl)acetamide

By similar reaction and treatment to that in the above-mentionedExamples, the title compound was obtained.

m.p.=134-135° C.

Example 65 Synthesis ofN-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

(1) Synthesis of Methyl1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate

By similar reaction and treatment to that in Example 1(5) using methyl1-(4-chloromethylphenyl)cyclopropanecarboxylate obtained in Example75(2) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(4-fluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.16-1.20(2H, m), 1.58-1.62(2H, m), 2.59-2.63(4H, m),3.09-3.13(4H, m), 3.55(2H, s), 3.62(3H, s), 6.83-6.98(4H, m),7.25-7.32(4H, m). MS(EI): 368(M⁺).

(2) Synthesis of1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

Methyl1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate(2.26 g) was dissolved in ethanol (18 ml) and a solution of sodiumhydroxide (0.49 g) in water (4.6 ml) was added, and the mixture washeated at 70° C. for 2 hr. The solvent was evaporated, and the residuewas dissolved in water (200 ml). The solution was neutralized withhydrochloric acid and extracted with ethyl acetate (300 ml). The extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated to give the title compound (1.73 g)as white crystals, m.p.=74-77° C.

¹H-NMR(CDCl₃)δ: 1.13-1.17(2H, m), 1.57-1.65(2H, m), 2.76-2.79(4H, m),3.11-3.12(4H, m), 3.62(2H, s), 6.81-6.98(4H, m), 7.22-7.34(4H, m),7.70(1H, br.s). MS(EI): 354(M⁺).

(3) Synthesis ofN-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

To a suspension of1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicacid (1.73 g) in water (1.7 ml) was added acetone (7 ml) and dissolvedtherein. A solution of triethylamine (0.75 ml) in acetone (10 ml) wasadded under ice-cooling and a solution of ethyl chlorocarbonate (0.56ml) in acetone (4 ml) was added dropwise over 15 min. The mixture wasstirred at 0° C. for 30 min. To this solution was added dropwise asolution of sodium azide (0.48 g) in water (3 ml) under ice-cooling over10 min. The mixture was stirred for 30 min. The reaction mixture waspoured into ice water (100 ml) and extracted with diethyl ether. Theextract was dried over anhydrous magnesium sulfate and the solvent wasevaporated to give an oil. The oil was dissolved in toluene (17 ml) andheated at 100° C. for 1 hr. The reaction mixture was ice-cooled andmethylmagnesium iodide (1M, diethyl ether solution) (4.3 ml) was added.The mixture was stirred at room temperature for 30 min. The reactionmixture was poured into aqueous ammonium chloride and extracted withwater and ethyl acetate (100 ml). The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated and the obtained residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:methanol=100:1) andrecrystallized from ethyl acetate-isopropyl ether to give the titlecompound (0.52 g) as white crystals.

m.p.=124-126° C. ¹H-NMR(CDCl₃)δ: 1.26 and 1.36(4H, s and d, J=4.0 Hz),2.00(3H, s), 2.56-2.62(4H, m), 3.08-3.13(4H, m), 3.51 and 3.54(2H, s ands), 6.09 and 6.12(1H, s and s), 6.83-6.98(4H, m), 7.10-7.32(4H, m).MS(EI): 367(M⁺); Elemental analysis: Calculated: C; 71.91, H; 7.13, N;11.44; Found: C; 71.57, H; 7.23, N; 11.41.

Example 66 Synthesis ofN-(1-(4-((4-(2,4-Difluorophenyl)-piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

(1) Synthesis of Methyl1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate

By similar reaction and treatment to that in Example 1(5) using methyl1-(4-chloromethylphenyl)cyclopropanecarboxylate obtained in Example75(2) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(2,4-difluorophenyl)piperazine dihydrochloride instead ofphenylpiperazine, the title compound was obtained as an orange oil.

¹H-NMR(CDCl₃)δ: 1.11-1.20(2H, m), 1.58-1.62(2H, m), 2.61-2.65(4H, m),3.02-3.06(4H, m), 3.56(2H, s), 3.62(3H, s), 6.74-6.94(3H, m),7.25-7.32(4H, m). MS(EI): 386(M⁺).

(2) Synthesis of1-(4-((4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

By similar reaction and treatment to that in Example 65(2) using methyl1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylateinstead of methyl1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate,the title compound was obtained as white crystals.

m.p.=70-74° C.; ¹H-NMR(CDCl₃)δ: 1.13-1.19(2H, m), 1.57-1.65(2H, m),2.81(4H, m), 3.04-3.05(4H, m), 3.62(2H, s), 6.73-7.36(8H, m); MS(EI):372(M⁺).

(3) Synthesis ofN-(1-(4-((4-(2,4-Difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 65(3) using1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicacid instead of1-(4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicacid, the title compound was obtained as white crystals.

m.p.=124-125° C.; ¹H-NMR(CDCl₃)δ: 1.26 and 1.32(4H, s and d, J=4.0 Hz),2.00(3H, s), 2.58-2.63(4H, m), 3.00-3.04(4H, m), 3.52 and 3.55(2H, s ands), 6.11 and 6.13(1H, s and s), 6.75-6.93(3H, m), 7.09-7.32(4H, m).MS(EI): 385(M⁺); Elemental analysis: Calculated: C; 68.55, H; 6.54, N;10.90; Found: C; 68.50, H; 6.61, N; 10.96.

Example 67 Synthesis of N-(1-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide

(1) Synthesis of N-(1-Phenylcyclopropyl)acetamide

By similar reaction and treatment to that in Example 65(3) using1-phenylcyclopropanecarboxylic acid instead of1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylicacid, the title compound was obtained as pale-yellow crystals,m.p.=94-95° C.

¹H-NMR(CDCl₃)δ: 1.24 and 1.33-1.36(4H, s and m), 1.96 and 1.97(3H, s ands), 6.36(1H, br.s), 7.13-7.35(5H, m). MS(EI): 175(M⁺).

(2) Synthesis of N-(1-(4-Acetylphenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 16(2) usingN-(1-phenylcyclopropyl)acetamide instead of N-phenylmethylacetamide, thetitle compound was obtained as white crystals, m.p.=128-131° C.

¹H-NMR(CDCl₃)δ: 1.33 and 1.46(4H, s and s), 1.96 and 2.02(3H, s and s),2.56 and 2.59(3H, s and s), 6.26 and 6.36(1H, br.s and br.s),7.21-7.28(2H, m), 7.84-7.93(2H, m). MS(EI): 217(M⁺).

(3) Synthesis of N-(1-(4-(1-Hydroxyethyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 16(3) usingN-(1-(4-acetylphenyl)cyclopropyl)acetamide instead ofN-((4-acetylphenyl)methyl) acetamide, the title compound was obtained aswhite crystals, m.p.=114-116° C.

¹H-NMR(CDCl₃)δ: 1.25 and 1.35(4H, s and d, J=3.3 Hz), 1.46 and 1.50(3H,d, J=6.6 Hz and s), 1.87 and 1.92(1H, d, J=4.0 Hz and d, J=3.3 Hz), 1.97and 1.98(3H, s and s), 4.82-4.90(1H, m), 6.17(1H, br.s), 7.11-7.35(4H,m). MS(EI): 219(M⁺).

(4) Synthesis of N-(1-(4-(1-Chloroethyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 16(4) usingN-(1-(4-(1-hydroxyethyl)phenyl)cyclopropyl)acetamide instead ofN-((4-(1-hydroxyethyl)phenyl)methyl)acetamide, the title compound wasobtained as white crystals, m.p.=104-107° C.

¹H-NMR(CDCl₃)δ: 1.25 and 1.35-1.38(4H, s and m), 1.81 and 1.85(3H, d,J=6.6 Hz and s), 1.98(1H, s), 5.06(1H, q, J=6.6 Hz), 6.25 and 6.29(1H,br.s and br.s), 7.11-7.40(4H, m). MS(EI): 237(M⁺).

(5) Synthesis ofN-(1-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=149-150° C.

¹H-NMR(CDCl₃)δ: 1.26(3H, s), 1.35-1.39(4H, m), 2.00(3H, s),2.48-2.66(4H, m), 3.05-3.10(4H, m), 3.32-3.45(1H, m), 6.12-6.14(1H, m),6.81-6.98(4H, m), 7.08-7.30(4H, m). MS(EI): 381(M⁺); Elemental analysis:Calculated: C; 72.41, H; 7.40, N; 11.01; Found: C; 72.33, H; 7.39, N;10.94.

Example 68 Synthesis ofN-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)acetamidedihydrochloride monohydrate

(1) Synthesis of 2-(4-Methylphenyl)-2-methylpropionitrile

A suspension of 60% sodium hydride (50 g) and tetrahydrofuran (225 ml)was heated to 40° C. and a solution of 4-methylphenylacetonitrile (74.5g) in tetrahydrofuran (75 ml) was added dropwise over 30 min. Themixture was stirred at 40° C. for 30 min and a solution of methyl iodide(78 ml) in tetrahydrofuran (75 ml) was added dropwise over 30 min. Themixture was stirred at 40° C. for 1 hr. The reaction mixture was pouredinto water (2000 ml) and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the obtained residue was purified bydistillation under reduced pressure to give the title compound (83.66 g)as a colorless oil.

Boiling point=88-91° C./4 mmHg; ¹H-NMR(CDCl₃)δ: 1.70(6H, s), 2.34(3H,s), 7.19(2H, d, J=7.9 Hz), 7.35(2H, d, J=7.9 Hz). MS(EI): 159(M⁺).

(2) Synthesis of 2-(4-Methylphenyl)-2-methylpropionic Acid

A solution of 2-(4-methylphenyl)-2-methylpropionitrile (53.61 g), sodiumhydroxide (40.4 g), diethylene glycol (160.8 ml) and water (60.6 ml) wasrefluxed for 18 hr. The reaction mixture was poured into water (3000 ml)and conc. hydrochloric acid (90 ml) was added. The generated crystalswere collected by filtration to give the title compound (60.0 g) aspale-brown crystals, m.p.=78-81° C.

¹H-NMR(CDCl₃)δ: 1.57(6H, s), 2.32(3H, s), 7.14(2H, d, J=8.6 Hz),7.28(2H, d, J=8.6 Hz). MS(EI): 178(M⁺).

(3) Synthesis of Methyl 2-(4-Methylphenyl)-2-methylpropionate

A solution of 2-(4-methylphenyl)-2-methylpropionic acid (60.0 g),sulfuric acid (0.6 ml) and methanol (300 ml) was refluxed for 19 hr. Thesolvent was evaporated, and water (200 ml) was added and the mixture wasextracted with chloroform. The extract was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedto give the title compound (61.52 g) as a pale-brown oil.¹H-NMR(CDCl₃)δ:1.56(6H, s), 2.32(3H, s), 3.64(3H, s), 7.13(2H, d, J=8.6Hz), 7.22(2H, d, J=8.6 Hz). MS(EI): 192(M⁺).

(4) Synthesis of Methyl 2-(4-Azidomethylphenyl)-2-methylpropionate

A solution of methyl 2-(4-methylphenyl)-2-methylpropionate (58.5 g),N-bromosuccinimide (54.2 g), benzoyl peroxide (1.2 g) and carbontetrachloride (300 ml) was refluxed for 40 min. After being cooled, thereaction mixture was filtrated. The filtrate was washed with an aqueoussodium sulfite solution and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give methyl2-(4-bromomethylphenyl)-2-methylpropionate (80.0 g) as a pale-brown oil.To a solution of this oil in dimethylformamide (500 ml) was added sodiumazide (21.14 g) and the mixture was stirred at 80° C. for 40 min. Thereaction mixture was poured into water (1000 ml) and extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theobtained residue was purified by silica gel column chromatography(developing solvent; hexane,hexane:ethyl acetate=20:1) to give the titlecompound (48.1 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.58(6H, s), 3.64(3H, s), 4.31(2H, s), 7.25-7.37(4H, m).

(5) Synthesis of Methyl 2-(4-Aminomethylphenyl)-2-methylpropionate

A solution of methyl 2-(4-azidomethylphenyl)-2-methylpropionate (48.1g)and triphenylphosphine (59.5 g) in a mixed solvent of tetrahydrofuran(480 ml) and water (24 ml) was refluxed for 30 min. The solvent wasevaporated, and the obtained residue was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=10:1,chloroform:methanol:aqueous ammonia=10:1:0.3) to give the title compound(29.4 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.57(6H, s), 2.42(3H, s), 3.63(3H, s), 3.83(2H, s),7.25-7.32(4H, m).

(6) Synthesis of Methyl 2-(4-Acetamidomethylphenyl)-2-methylpropionate

To a solution of methyl 2-(4-aminomethylphenyl)-2-methylpropionate (29.4g) and triethylamine (23.8 ml) indichloroethane (300 ml) was addeddropwise acetyl chloride (11.1 ml) at 5° C. over 30 min. The mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto water and the organic layer was separated. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the obtained residue was purified bysilica gel column chromatography (developing solvent; ethylacetate:hexane=3:1, ethyl acetate) to give the title compound (23.47 g)as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.56(6H, s), 1.98(3H, s), 3.63(3H, s), 4.37(2H, d, J=5.3Hz), 7.21-7.31(4H, m). MS(EI): 249(M⁺).

(7) Synthesis of 2-(4-Acetamidomethylphenyl)-2-methylpropionic Acid

To a solution of methyl 2-(4-acetylaminomethylphenyl)-2-methylpropionate(23.47 g) in ethanol (160 ml) was added a solution of sodium hydroxide(7.53 g) in water (94 ml) and the mixture was stirred at 70° C. for 1hr. The solvent was evaporated, and conc. hydrochloric acid was added.The resulting crystals were collected by filtration to give the titlecompound (14.0 g) as pale-yellow crystals, m.p.=166-169° C.

¹H-NMR(DMSO-d₆)δ: 1.45(6H, s), 1.85(3H, s), 4.21(2H, d, J=5.9 Hz),7.20(2H, d, J=8.6 Hz), 7.29(2H, d, J=8.6 Hz), 8.28(1H, br), 12.27(1H,br.s). MS(EI): 235(M⁺).

(8) Synthesis ofN-(4-(1-Benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide

To a solution of 2-(4-acetylaminomethylphenyl)-2-methylpropionic acid(14 g) in a mixed solvent of acetone (40 ml) and dimethylformamide (30ml) was added triethylamine (8.75 ml) under ice-cooling and a solutionof ethyl chlorocarbonate (6.76 g) in acetone (20 ml) was added dropwiseover 10 min. The mixture was stirred at 0° C. for 15 min. To thissolution was added dropwise a solution of sodium azide (4.26 g) in water(28 ml) under ice-cooling over 10 min, and the mixture was stirred for30 min. The reaction mixture was poured into ice water (500 ml) andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated and the obtained oil was dissolved in toluene (100 ml) andheated at 80° C. for 2 hr. To this solution was added benzyl alcohol(6.77 ml) and the mixture was stirred at 80° C. for 42 hr. To thereaction mixture was added isopropyl alcohol to allow crystallization togive the title compound (14.62 g) as white crystals, m.p.=132-135° C.

¹H-NMR(DMSO-d₆)δ: 1.51(6H, s), 1.86(3H, s), 4.21(4H, d, J=5.3 Hz),4.93(2H, m), 7.14-7.42(9H, m), 7.65(1H, br.s), 8.26-8.30(1H, br).

(9) Synthesis of N-(4-(1-Amino-1-methylethyl)phenylmethyl)acetamide

To a solution ofN-(4-(1-benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide(9.57 g) in methanol (200 ml) and chloroform (200 ml) was added 10%palladium-carbon (5.0 g) and the mixture was stirred for 5 hr whileintroducing a hydrogen gas. The reaction mixture was passed throughCelite and the solvent was evaporated to give the title compound (5.8 g)as a pale-yellow amorphous solid.

¹H-NMR(DMSO-d₆)δ: 1.63(6H, s), 1.87(3H, s), 4.23(2H, d, J=5.9 Hz),7.28(2H, d, J=7.9 Hz), 7.52(2H, d, J=7.9 Hz), 8.47(1H, br), 8.77(2H,br.s).

(10) Synthesis of EthylN-Ethoxycarbonylmethyl-N-(4-fluorophenyl)aminoacetate

To a solution of 4-fluoroaniline (10 g) and bromoethyl acetate (31.56 g)in dimethylformamide (120 ml) was added potassium carbonate (31.09 g)and the mixture was stirred at 80° C. for 1.5 hr. Bromoethyl acetate(13.5 g) and potassium carbonate (6.22 g) were further added and themixture was stirred for 3 hr. The reaction mixture was poured into water(500 ml) and extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the obtained residue was purified by silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=7:1,ethyl acetate) to give the title compound (13.51 g) as a yellow oil.

¹H-NMR(CDCl₃)δ: 1.26(6H, t, J=7.3 Hz), 4.10(2H, s), 4.20(4H, q, J=7.3Hz), 6.51-6.61(2H, m), 6.86-6.96(2H, m). MS(EI): 283(M⁺).

(11) Synthesis of N,N-bis(2-Hydroxyethyl)-4-fluorophenylamine

To a solution of N-ethoxycarbonylmethyl-N-(4-fluorophenyl)-aminoethylacetate (13.51 g) in tetrahydrofuran (135 ml) was added lithiumborohydride (4.15 g) and the mixture was stirred at 60° C. for 1 hr. Thereaction mixture was poured into water (300 ml) and extracted with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated to give thetitle compound (9.2 g) as a yellow oil.

¹H-NMR(CDCl₃)δ: 3.42-3.46(4H, m), 3.71-3.74(4H, m), 4.24(2H, br.s),6.56-6.64(2H, m), 6.87-6.94(2H, m). MS(EI): 199(M⁺).

(12) Synthesis of N,N-bis(2-Chloroethyl)-4-fluorophenylamine

To a solution of N,N-bis(2-hydroxyethyl)-4-fluorophenylamine (9.2 g) inmethylene chloride (92 ml) was added dropwise thionyl chloride (7.1 ml)over 10 min under ice-cooling. The mixture was stirred at roomtemperature for 1 hr and the reaction mixture was further refluxed for1.5 hr. The mixture was poured into aqueous sodium hydrogencarbonate tomake it alkaline and the organic layer was separated. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=10:1) to give the title compound (4.88 g) as anorgange oil.

¹H-NMR(CDCl₃)δ: 3.56-3.70(8H, m), 6.60-6.67(2H, m), 6.91-7.00(2H, m).

(13) Synthesis ofN-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)acetamideDihydrochloride Monohydrate

To a solution of N-(4-(1-amino-1-methylethyl)phenylmethyl)-acetamide(1.55 g) and N,N-di(2-chloroethyl)-4-fluoroaniline (1.5 g) in dimethylsulfoxide (30 ml) were added potassium carbonate (3.12 g) and potassiumiodide (2.50 g) and the mixture was stirred at 80° C. for 24 hr. Thereaction mixture was poured into water (300 ml) and extracted with ethylacetate. The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated and the obtainedresidue was purified by silica gel chromatography (developing solvent;ethyl acetate:hexane=3:1) and treated with 1M hydrochloric acid-ether inethanol to give the title compound (0.33 g) as white crystals.

m.p.=179-181° C.; ¹H-NMR(DMSO-d₆)δ: 1.87 and 1.89(9H, s and s),2.88-2.96(2H, m), 3.35-3.44(4H, m), 3.61-3.66(2H, m), 4.28(2H, d, J=5.9Hz), 6.95-7.12(4H, m), 7.36(2H, d, J=8.6 Hz), 7.82(2H, d, J=8.6 Hz),8.48(1H, t, J=5.9 Hz). MS(EI): 369(M⁺); Elemental analysis: Calculated:C; 57.39, H; 7.01, N; 9.13; Found: C; 57.63, H; 6.96, N; 9.19.

Example 69 Synthesis ofN-(1-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2-pyrimidyl)piperazine instead of phenylpiperazine andN-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 66(3)instead of N-(4-chloromethylphenylmethyl)acetamide, the title compoundwas obtained as white crystals.

m.p.=124-126° C.; ¹H-NMR(DMSO-d₆)δ: 1.33(3H, d, J=7.3 Hz), 1.84(3H, s),2.40(4H, t, J=5.3 Hz), 3.47(2H, s), 3.72(4H, t, J=5.0 Hz), 4.91(1H, dq,J=7.3, 7.3 Hz), 6.60(1H, t, J=5.0 Hz), 7.27(4H, s), 8.25(1H, d, J=7.9Hz), 8.34(2H, d, J=4.6 Hz). IR(KBr): 3309, 1643, 1587, 1547 cm⁻¹;MS(EI): 339(M⁺); Elemental analysis: Calculated: C; 67.23, H; 7.42, N;20.63; Found: C; 67.18, H; 7.50, N; 20.52.

Example 70 Synthesis ofN-(1-(4-(1-(4-(Pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=124-125° C.

¹H-NMR(CDCl₃)δ: 1.26(3H, s), 1.34-1.41(4H, m), 2.00(3H, s),2.38-2.54(4H, m), 3.33-3.45(1H, m), 3.76-3.81(4H, m), 6.10 and 6.16(1H,s and s), 6.42-6.46(1H, m), 7.08-7.30(4H, m), 8.27(2H, d, J=4.6 Hz).MS(EI): 365(M⁺); Elemental analysis: Calculated: C; 69.01, H; 7.45, N;19.16; Found: C; 68.97, H; 7.47, N; 19.05.

Example 71 Synthesis ofN-(1-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

(1) Synthesis of N-(1-(4-Chloromethylphenyl)cyclopropyl)acetamide

To a solution of N-(1-phenylcyclopropyl)acetamide (5.0 g) in methylenechloride (35 ml) was added titanium tetrachloride (6.26 ml) underice-cooling and to this solution was added dropwise a solution ofmethoxymethyl chloride (4.33 ml) in methylene chloride (15 ml) over 10min under ice-cooling. The mixture was stirred at room temperature for14 hr. The reaction mixture was poured into ice water and extracted withchloroform (50 ml). The extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe obtained residue was purified by silica gel column chromatography(developing solvent; ethyl acetate) to give the title compound (3.71 g)as white crystals, m.p.=124-127° C.

¹H-NMR(CDCl₃)δ: 1.25 and 1.37(4H, s and s), 1.98(3H, s), 4.54 and4.57(2H, s and s), 6.17-6.28(1H, m), 7.12-7.36(4H, m). MS(EI): 223(M⁺).

(2) Synthesis ofN-(1-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)cyclopropyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=145-146° C.

¹H-NMR(CDCl₃)δ: 1.26 and 1.36(4H, s and d, J=5.3 Hz), 2.00(3H, s),2.45-2.51(4H, m), 3.49 and 3.52(2H, s and s), 3.79-3.84(4H, m), 6.14(1H,s), 6.44-6.48(1H, m), 7.09-7.32(4H, m), 8.29(2H, d, J=4.6 Hz). MS(EI):351(M⁺); Elemental analysis: Calculated: C; 68.35, H; 7.17, N; 19.93;Found: C; 68.30, H; 7.07, N; 19.77.

Example 72 Synthesis ofN-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 4-Acetamidomethylbenzoic Acid

To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in ethyl acetate(100 ml) was added an aqueous solution (100 ml) of sodium hydroxide (12g) and acetic anhydride (14 ml) was further added at 5-7° C. Thereaction mixture was stirred at room temperature for 1 hr. The reactionmixture was made acidic with 10% hydrochloric acid and extracted withethyl acetate:ethanol (10:1). The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a pale-yellow solid (27.2 g). The obtained solid wascrystallized from ethyl acetate:ethanol (1:1, 500 ml) to give the titlecompound (16.7 g) as white crystals, m.p.=200-202° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 4.32(2H, d, J=5.9 Hz), 7.36(2H, d, J=7.9Hz), 7.89(2H, d, J=8.6 Hz), 8.41(1H, m), 12.84(1H, br.s); IR(KBr): 3298,1691, 1646, 1539 cm⁻¹; MS(EI): 193(M⁺); Elemental analysis: Calculated:C; 62.17, H; 5.74, N; 7.25; Found: C; 62.01, H; 5.71, N; 7.21.

(2) Methyl 4-Acetamidomethylbenzoate

4-Acetamidomethylbenzoic acid (4.0 g) was dissolved in 0.5% hydrogenchloride-methanol solution (100 ml). The mixture was stirred at 40° C.for 3.5 hr and poured into ice water (300 ml) and extracted with ethylacetate. The extract was washed with a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated to give a pale-yellow solid(4.3 g). The obtained solid was crystallized from ethyl acetate (50 ml)to give the title compound (3.2 g) as a pale-yellow white crystals,m.p.=110-111° C.

¹H-NMR(DMSO-d₆)δ: 1.90(3H, s), 3.84(3H, s), 4.33(2H, d, J=5.9 Hz),7.39(2H, d, J=8.6 Hz), 7.92(2H, d, J=7.9 Hz), 8.43(1H, m); IR(KBr):3277, 1727, 1643, 1556 cm⁻¹; MS(EI): 207(M⁺); Elemental analysis:Calculated: C; 63.76, H; 6.32, N; 6.76; Found: C; 63.76, H; 6.38, N;6.76.

(3) N-(4-Hydroxymethylphenylmethyl)acetamide

To a suspension of aluminum lithium hydride (570 mg) in tetrahydrofuran(80 ml) was added a solution of methyl 4-acetamidomethylbenzoate (3.1 g)in tetrahydrofuran (20 ml) under ice-cooling. The reaction mixture wasstirred at room temperature for 1.5 hr. A saturated aqueous sodiumsulfate solution (7 ml) was added at 10° C., and the mixture was stirredat room temperature for 1 hr. The sediment was filtered off and thesolvent was evaporated to give the title compound (2.8 g) as a whitesolid.

¹H-NMR(DMSO-d₆)δ: 1.86(3H, s), 4.22(2H, d, J=5.9 Hz), 4.46(2H, s),5.13(1H, br.s), 7.19(2H, d, J=7.9 Hz), 7.25(2H, d, J=8.6 Hz), 8.30(1H,m); MS(EI): 179(M⁺).

(4) N-(4-Chloromethylphenylmethyl)acetamide

To a solution of N-(4-hydroxymethylphenylmethyl)acetamide (1.5 g) inchloroform (50 ml) was added thionyl chloride (0.73 ml) and the mixturewas refluxed under heating for 1 hr. The solvent was evaporated and theobtained residue was crystallized from ethyl acetate to give the titlecompound (1.8 g) as pale-yellow crystals.

m.p.=116-118° C.; ¹H-NMR(CDCl₃)δ: 2.01(3H, s), 4.40(2H, d, J=5.9 Hz),4.56(2H, s), 6.20(1H, br.s), 7.26(2H, d, J=8.6 Hz), 7.34(2H, d, J=7.9Hz); MS(EI): 197(M⁺).

(5)N-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (15.0 g),1-(2-pyrimidyl)piperazine dihydrochloride (19.8 g) and potassiumcarbonate (42.0 g) in dimethylformamide (200 ml) was stirred at 80° C.for 8.5 hr. The reaction mixture was poured into water (500 ml) andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a brown oil (24.0 g). The obtained brown oil waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=20:1) to give a pale-brown oil (18.7 g). Theobtained pale-brown oil was crystallized from ethyl acetate: hexane(5:1, 100 ml) and the crystals were recrystallized from ethylacetate:hexane (10:1, 100 ml) to give the title compound (12.8 g) aswhite crystals,

m.p.=120-121° C. ¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.38-2.42(4H, m),3.47(2H, s), 3.70-3.73(4H, m), 4.24(2H, d, J=5.9 Hz), 6.60(1H, t, J=4.6Hz), 7.20-7.29(4H, m), 8.30(1H, t, J=5.3 Hz), 8.34(2H, d, J=4.6 Hz);IR(KBr): 3292, 2792, 1651, 1587 cm⁻¹; MS(EI): 325(M⁺); Elementalanalysis: Calculated: C; 66.44, H; 7.12, N; 21.52; Found: C; 66.48, H;7.19, N; 21.72.

Example 73 Synthesis ofN-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideDihydrochloride Monohydrate

To a solution ofN-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide(5.1 g) in ethanol (40 ml) was added 1M hydrogen chloride—ether (40 ml)and the solvent was evaporated under reduced pressure to give apale-brown substance (7.2 g). The obtained pale-brown substance wascrystallized and recrystallized from ethyl acetate/ethanol to give thetitle compound (3.8 g) as white crystals, m.p.=194-195° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 2.95-3.10(2H, m), 3.25-3.35(2H, m),3.40-3.55(2H, m), 4.25-4.32(4H, m), 4.65-4.71(2H, m), 5.20-5.40(3H, m),6.78(1H, t, J=5.3 Hz), 7.32(2H, d, J=7.9 Hz), 7.61(2H, d, J=7.9 Hz),8.45(2H, d, J=4.6 Hz), 8.50(1H, t, J=5.9 Hz), 11.80(1H, brs); IR(KBr):3417, 3290, 1627, 1544 cm⁻¹; MS(EI): 325(M⁺); Elemental analysis:Calculated: C; 51.93, H; 6.54, N; 16.82; Found: C; 52.26, H; 6.40, N;16.86.

Example 74 Synthesis of2-(4-(4-(Aminomethyl)phenylmethyl)-piperazin-1-yl)pyrimidine

N-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide(4.0 g) was dissolved in 10% hydrochloric acid (50 ml) and the solutionwas refluxed under heating for 12.5 hr. To the reaction mixture wasadded 10% aqueous sodium hydroxide solution to make it alkaline, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated and the obtained residue was crystallized from diisopropylether to give the title compound (2.2 g) as pale-yellow crystals,m.p.=70-72° C.

¹H-NMR(DMSO-d₆)δ: 2.38-2.42(4H, m), 2.70-3.10(2H, brs), 3.47(2H, s),3.70-3.73(6H, m), 6.62(1H, t, J=4.6 Hz), 7.23-7.30(4H, m), 8.34(2H, d,J=5.3 Hz); IR(KBr): 3358, 2939, 2817, 1585 cm⁻¹; MS(EI): 283(M⁺);Elemental analysis: Calculated: C; 67.81, H; 7.47, N; 24.71; Found: C;67.52, H; 7.42, N; 24.12.

Example 75 Synthesis ofN-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)propionamide1/4 Hydrate

A solution of2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (0.5 g),propionic chloride (0.18 ml) and triethylamine (0.3 ml) in methylenechloride (20 ml) was stirred at room temperature for 2 hr. The reactionmixture was washed with water and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give a pale-yellowsubstance (0.8 g). The obtained pale-yellow substance was crystallizedfrom hexane/ethyl acetate (1:1, 50 ml) to give the title compound (0.5g) as pale-yellow crystals.

m.p.=103-105° C.; ¹H-NMR(DMSO-d₆)δ: 1.03(3H, t, J=7.9 Hz), 2.15(2H, q,J=7.9 Hz), 2.40-2.43(4H, m), 3.49(2H, s), 3.70-3.74(4H, m), 4.25(2H, d,J=5.9 Hz), 6.60(1H, t, J=4.6 Hz), 7.19-7.30(4H, m), 8.25(1H, t, J=5.9Hz), 8.34(2H, d, J=4.6 Hz); IR(KBr): 3290, 2935, 1635, 1587 cm⁻¹;MS(EI): 339(M⁺); Elemental analysis: Calculated: C; 66.35, H; 7.47, N;20.36; Found: C; 66.31, H; 7.50, N; 19.97.

Example 76 Synthesis ofN-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)formamide

A mixture of acetic anhydride (0.30 ml) and formic acid (0.13 ml) wasstirred at 50-60° C. for 1 hr. To the obtained acetic formic anhydridewas added a solution of2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidin (0.42 g) inmethylene chloride (10 ml) under ice-cooling and the mixture was stirredat 5-10° C. for 2 hr. The reaction mixture was concentrated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (developing solvent; chloroform:methanol=9:1) togive a yellow oil. (0.46 g). The obtained yellow oil was crystallizedfrom ethyl acetate/diisopropyl ether to give the title compound (0.45 g)as pale-yellow crystals, m.p.=97-98° C.

¹H-NMR(DMSO-d₆)δ: 2.38-2.42(4H, m), 3.48(2H, s), 3.70-3.73(4H, m),4.30(2H, d, J=5.9 Hz), 6.60(1H, t, J=4.6 Hz), 7.22-7.31(4H, m), 8.15(1H,s), 8.34(2H, d, J=4.6 Hz), 8.45-8.55(1H, m); IR(KBr): 3383, 2868, 1664,1581 cm⁻¹; MS(EI): 311(M⁺); Elemental analysis: Calculated:° C.; 65.57,H; 6.80, N; 22.49; Found: C; 65.38, H; 6.78, N; 22.27.

Example 77 Synthesis of EthylN-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)succinamideDihydrochloride 1/2 Hydrate

A solution of2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (1.3 g),ethylsuccinyl chloride (0.7 ml) and triethylamine (0.7 ml) in methylenechloride (40 ml) was stirred at room temperature for 4.5 hr. To thereaction mixture was added chloroform (100 ml), washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a brown oil (2.0 g). Theobtained brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give a pale-brown oil(2.0 g). To the obtained pale-brown oil was added 1M hydrogenchloride—ether (12 ml) in ethanol and the mixture was concentrated underreduced pressure and crystallized from ethyl acetate/ethanol to give thetitle compound (1.4 g) as white crystals, m.p.=120-123° C.

¹H-NMR(DMSO-d⁶)δ: 1.17(3H, t, J=7.3 Hz), 2.40-2.55(4H, m), 2.95-3.10(2H,m), 3.30-3.35(2H, m), 3.45-3.55(2H, m), 4.05(2H, q, J=7.3 Hz),4.25-4.35(4H, m), 4.65-4.75(2H, m), 4.80-4.90(2H, m), 6.77(1H, t, J=4.6Hz), 7.31(2H, d, J=7.9 Hz), 7.60(2H, d, J=7.9 Hz), 8.45(2H, d, J=4.6Hz), 8.52(1H, t, J=5.9 Hz), 11.78(1H, brs); IR(KBr): 3421, 3292, 2981,1728, 1626 cm⁻¹; MS(EI): 411(M⁺); Elemental analysis: Calculated: C;53.55, H; 6.54, N; 14.19; Found: C; 53.81, H; 6.66, N; 14.28.

Example 78 Synthesis ofN-(4-((4-(4,6-Difluoropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) N-(4-((4-Acetylpiperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (7.7 g),1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) indimethylformamide (50 ml) was stirred at 80° C. for 5 hr. The reactionmixture was poured into water (250 ml) and extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a yellow oil. Theobtained yellow oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give the title compound(11.5 g) as a colorless transparent oil.

¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.06(3H, s), 2.37-2.44(4H, m),3.43-3.46(2H, m), 3.50(2H, s), 3.58-3.61(2H, m), 4.41(2H, d, J=5.9 Hz),6.00(1H, brs), 7.22-7.30(4H, m); MS(EI): 289(M⁺).

(2) N-(4-((Piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution ofN-(4-((4-acetylpiperazin-1-yl)methyl)-phenylmethyl)acetamide (11.5 g)and sodium hydroxide (4.0 g) in ethanol (20 ml)-water (20 ml) wasrefluxedunder heating for 18 hr. The reaction mixture was extracted withchloroform and the extract was dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a pale-brown oil (9.1 g). The obtainedpale-brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol:aqueous ammonia=9:1:0.3) togive the title compound (7.4 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 2.01(3H, s), 2.35-2.40(4H, m), 2.84-2.87(4H, m),3.46(2H, s), 4.40(2H, d, J=5.30 Hz), 5.91(1H, brs), 7.20-7.30(4H, m);MS(EI): 247(M⁺).

(3)N-(4-((4-(4,6-Difluoropyrimidin-2-yl)piperazin-1-yl)methyl)-phenylmethyl)acetamide

To a solution of 2,4,6-trifluoropyrimidine (1.4 g) and potassiumcarbonate (2.1 g) in acetonitrile (30 ml) was added a solution ofN-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (2.5 g) inacetonitrile (20 ml) over 5 min under ice-cooling. The mixture wasstirred at the same temperature for 1.5 hr. The reaction mixture waspoured into water (100 ml) and extracted with ethyl acetate. The extractwas washed with brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a white solid (3.2 g). The obtained whitesolid was purified by silica gel column chromatography (developingsolvent; chloroform:methanol=50:1) to give a crude purification product(1.3 g) ofN-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideand a crude purification product (1.1 g) ofN-(4-((4-(2,6-difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide.The crude purification product ofN-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamidewas crystallized from ethyl acetate:diisopropyl ether to give the titlecompound (1.0 g) as white crystals, m.p.=128-129° C.

¹H-NMR(CDCl₃)δ: 2.03(3H, s), 2.46(4H, t, J=5.3 Hz), 3.52(2H, s),3.79(4H, t, J=5.3 Hz), 4.43(2H, d, J=5.3 Hz), 5.66(1H, t, J=1.3 Hz),5.75(1H, brs), 7.23-7.32(4H, m); IR(KBr): 3288, 2918, 1635, 1552 cm⁻¹;MS(EI): 361(M⁺); Elemental analysis: Calculated: C; 59.82, H; 5.86, N;19.38; Found: C; 59.83, H; 5.85, N; 19.44.

Example 79 Synthesis ofN-(4-((4-(2,6-Difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

The roughly purified product (1.1 g) ofN-(4-((4-(2,6-difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideobtained in Example 78(3) was crystallized from ethylacetate:diisopropyl ether to give the title compound (1.0 g) as whitecrystals, m.p.=127-128° C.

¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.50(4H, t, J=5.3 Hz), 3.53(2H, s),3.55-3.70(4H, m), 4.42(2H, d, J=5.9 Hz), 5.87(1H, d, J=2.0 Hz),5.85-6.95(1H, brs), 7.23-7.31(4H, m); IR(KBr): 3259, 2946, 2823, 1624,1560 cm⁻¹; MS(EI): 361(M⁺); Elemental analysis: Calculated: C; 59.82, H;5.86, N; 19.38; Found: C; 59.89, H; 5.86, N; 19.44.

Example 80 Synthesis ofN-(4-((4-(4,6-Dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

To a solution of 2,4,6-trichloropyrimidine (1.0 g) and potassiumcarbonate (0.84 g) in acetonitrile (20 ml) was added a solution ofN-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.0 g) obtained inExample 78(2) in acetonitrile (20 ml) under ice-cooling over 5 min. Themixture was stirred at the same temperature for 30 min. The reactionmixture was poured into water (100 ml) and extracted with ethyl acetate.The extract was washed with brine and dried over anhydrous sodiumsulfate. The solvent was evaporated to give a pale-brown oil (1.6g). Theobtained pale-brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=50:1) to give a crudepurification product (0.28 g) ofN-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideand a crude purification product (0.9 g) ofN-(4-((4-(2,6-dichloropyriinidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide.The crude purification product ofN-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamidewas crystallized from ethyl acetate:hexane to give the title compound(0.2 g) as white crystals, m.p.=139-140° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.40-2.43(4H, m), 3.48(2H, s),3.68-3.72(4H, m), 4.23(2H, d, J=5.9 Hz), 6.90(1H, s), 5.75(1H, brs),7.19-7.29(4H, m), 8.30(1H, t, J=5.9 Hz); IR(KBr): 3259, 2858, 1639, 1570cm⁻¹; MS(EI): 394(M⁺); Elemental analysis: Calculated: C; 54.83, H;5.37, N; 17.76; Found: c;54.93, H; 5.43, N; 17.37.

Example 81 Synthesis ofN-(4-((4-(Thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/2 Hydrate

(1) 1-(Thiazol-2-yl)piperazine

To piperazine (48 g) dissolved by heating at 110° C. was added dropwise2-bromothiazole (5 ml) over 20 min. The mixture was stirred at 150° C.for 1 hr, poured into water (150 ml) and extracted with chloroform. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated to give the title compound (9.5 g)as a pale-yellow oil.

¹H-NMR(DMSO-d₆)δ: 2.78(4H, t, J=5.3 Hz), 3.29(4H, t, J=5.3 Hz), 6.80(1H,d, J=4.0 Hz), 7.15(1H, d, J=4.0 Hz); MS(EI): 169(M⁺).

(2) N-(4-((4-(Thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/2 Hydrate

A solution of N-(4-chloromethylphenylmethyl)acetamide(1.8 g),1-(thiazol-2-yl)piperazine (1.5 g) and potassium carbonate (1.8 g) indimethylformamide (20 ml) was stirred at 80° C. for 2.5 hr. The reactionmixture was poured into water (100 ml) and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a brown oil. Theobtained brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=9:1) to give a pale-brown oil(2.3 g). The obtained pale-brown oil was dissolved in ethanol (200 ml)and 1M hydrogen chloride—ether (7 ml) was added. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate:ethanol (1:1, 100 ml) and the crystals wererecrystallized from ethyl acetate:ethanol:methanol (1:1:1, 100 ml) togive the title compound (1.2 g) as white crystals, m.p.=120-121° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 3.00-3.35(4H, m), 3.50-3.65(2H, m),3.70-3.80(4H, m), 3.90-4.10(2H, m), 4.28(2H, d, J=5.9 Hz), 4.35(2H, s),6.99(1H, d, J=4.0 Hz), 7.24(1H, d, J=4.0 Hz), 7.32(1H, d, J=7.9 Hz),7.61(1H, d, J=7.9 Hz), 8.48(1H, t, J=5.9 Hz), 11.86(1H, brs); IR(KBr):3311, 2526, 2507, 1641, 1521 cm⁻¹; MS(EI): 330(M⁺); Elemental analysis:Calculated: C; 54.32, H; 6.44, N; 14.90; Found: C; 54.10, H; 6.31, N;14.73.

Example 82 Synthesis ofN-(4-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g),1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g) indimethylformamide (20 ml) was stirred at 60-70° C. for 2.5 hr. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a brown oil. Theobtained brown oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=20:1) to give a pale-yellow oil(2.5 g). The obtained pale-yellow oil was crystallized from ethylacetate and the crystals were recrystallized from ethyl acetate to givethe title compound (1.4 g) as white crystals, m.p.=100-101° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 2.40-2.45(2H, m), 2.45-2.30(2H, m),3.40-3.50(4H, m), 4.23(2H, d, J=5.9 Hz), 6.62(1H, dd, J=5.3, 7.3 Hz),6.78(1H, d, J=8.6 Hz), 7.20-7.29(4H, m), 7.47-7.54(1H, m), 8.09(1H, dd,J=1.3, 4.6 Hz), 8.25-8.35(1H, m); IR(KBr): 3319, 2940, 2809, 1645, 1594cm⁻¹; MS(EI): 324(M⁺); Elemental analysis: Calculated: C; 70.34, H;7.46, N; 17.27; Found: C; 70.10, H; 7.50, N; 17.05.

Example 83 Synthesis ofN-(4-((4-(Pyridin-3-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide 1/2Hydrate

(1) 1-(Pyridin-3-yl)piperazine

A suspension of 3-aminopyridine (2.0 g) and bis(2-chloroethyl)aminehydrochloride (3.8 g) in o-xylene (40 ml) was stirred at 140° C. for 20hr. The reaction mixture was extracted with water and the aqueous layerwas made alkaline with a 2N aqueous sodium hydroxide solution andextracted with chloroform. The extract was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe obtained residue was purified by silica gel column chromatography(developing solvent; chloroform:methanol:aqueous amnmonia=9:1:0.5) togive the title compound (0.55 g) as a black brown oil.

¹H-NMR(DMSO-d₆)δ: 2.83(4H, d, J=5.3 Hz), 3.08(4H, d, J=5.3 Hz),7.17-7.21(1H, m), 7.26-7.30(1H, m), 7.97(1H, d, J=2.6 Hz), 8.27(1H, d,J=3.3 Hz); MS(EI): 163(M⁺).

(2) N-(4-((4-(Pyridin-3-yl)piperazin-1-)methyl)phenylmethyl)acetamide1/2 Hydrate

A solution of N-(4-chloromethylphenylmethyl) acetamide (0.67 g),1-(3-pyridyl)piperazine (0.55 g) and potassium carbonate (0.93 g) indimethylformamide (10 ml) was stirred at 80° C. for 4 hr. The reactionmixture was poured into water and extracted with chloroform. The extractwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated to give a black oil. The obtained black oilwas purified by silica gel column chromatography (developing solvent;chloroform:methanol=4:1) to give a brown solid. The obtained brown solidwas crystallized from ethyl acetate-methanol to give the title compound(200 mg) as white crystals, m.p.=139-140° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.48-2.51(4H, m), 3.15-3.20(4H, m),3.49(2H, s), 4.23(2H, d, J=5.9 Hz), 7.17-7.31(6H, m), 7.98(1H, d, J=3.3Hz), 8.27(1H, d, J=2.6 Hz), 8.30(1H, t, J=5.9 Hz); IR(KBr): 3455, 3232,3041, 1660, 1568 cm⁻¹; MS(EI): 324(M⁺); Elemental analysis: Calculated:C; 68.44, H; 7.56, N; 16.80; Found: C; 68.32, H; 7.59, N; 16.72.

Example 84 Synthesis ofN-(4-((4-(Pyridin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-(Pyridin-4-yl)piperazine

To piperazine (3.6 g) dissolved at 110° C. was added 4-bromopyridine(1.0 g) and the mixture was stirred at 140-150° C. for 1 hr. Thereaction mixture was poured into water and extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give the title compound(0.64 g) as a pale-yellow solid.

¹H-NMR(DMSO-d₆)δ: 2.78(4H, t, J=5.3 Hz), 3.20(4H, t, J=5.3 Hz), 6.77(2H,dd, J=1.3, 6.6 Hz), 8.14(2H, d, J=6.6 Hz); MS(EI): 163(M⁺).

(2) N-(4-((4-(Pyridin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl) acetamide (0.85 g),1-(pyridin-4-yl)piperazine (0.64 g) and potassium carbonate (0.81 g) indimethylformamide (10 ml) was stirred at 60-70° C. for 5 hr. Thereaction mixture was poured into water and extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=9:1)to give a yellow solid(0.6 g). The obtainedyellow solid was crystallized from ethyl acetate-methanol to give thetitle compound (0.37 g) as white crystals, m.p.=164-166° C.

¹H-NMR(DMSO-d₆)δ: 1.89(3H, s), 2.43-2.46(2H, m), 2.49-2.51(2H, m),3.27-3.30(4H, m), 3.49(2H, s), 4.23(2H, d, J=5.9 Hz), 6.78-6.79(2H, m),7.20-7.28(4H, m), 8.13-8.15(2H, m), 8.32(1H, m); IR(KBr): 3033, 2952,2931, 1664, 1599 cm⁻¹; MS(EI): 324(M⁺); Elemental analysis: Calculated:C; 70.34, H; 7.46, N; 17.27; Found: C; 70.29, H; 7.37, N; 17.26.

Example 85 Synthesis ofN-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/2 Ethyl Acetate

(1) 1-Acetyl-4-(6-fluoropyridin-2-yl)piperazine

A solution of 2,6-difluoropyridine (9.0 g), 1-acetylpiperazine (5.0 g)and potassium carbonate (8.1 g) in acetonitrile (100 ml) was refluxedunder heating for 18 hr. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givea pale-brown solid (8.7 g). The obtained pale-brown solid wascrystallized from ethyl acetate-hexane to give the title compound (5.5g) as pale-brown crystals.

m.p.=102-103° C.; ¹H-NMR(CDCl₃)δ: 2.14(3H, s), 3.48-3.55(2H, m),3.56-3.65(4H, m), 3.71-3.75(2H, m), 6.22(1H, dd, J=2.6, 7.9 Hz),6.43(1H, dd, J=2.6, 8.6 Hz), 7.57(1H, dd, J=7.9, 16.5 Hz); IR(KBr):3077, 2890, 2852, 1646, 1608 cm⁻¹; MS(EI): 223(M⁺); Elemental analysis:Calculated: C; 59.18, H; 6.32, N; 18.82; Found: C; 59.25, H; 6.34, N;18.83.

(2) 1-(6-Fluoropyridin-2-yl)piperazine

A solution of 1-acetyl-4-(6-fluoropyridin-2-yl)piperazine (5.5 g) andsodium hydroxide (3.0 g) in methanol (30 ml)—water (30 ml) was refluxedunder heating for 5 hr. The reaction mixture was poured into water andextracted with ethyl acetate. The solvent was evaporated to give thetitle compound (4.6 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 2.93-2.97(4H, m), 3.48-3.51(4H, m), 6.16(1H, dd, J=2.6,7.9 Hz), 6.40(1H, dd, J=2.6, 7.9 Hz), 7.52(1H, dd, J=7.9, 16.5 Hz).

(3)N-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideHydrochloride 1/2 Ethyl Acetate

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5 g),1-(6-fluoropyridin-2-yl)piperazine (1.3 g) and potassium carbonate (1.6g) in dimethylformamide (20 ml) was stirred at 80° C. for 6 hr. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=9:1) to give a pale-brown oil (2.9 g). The obtainedpale-brown oil was treated with 1M hydrogen chloride—ether andcrystallized from ethyl acetate-ethanol to give the title compound (2.2g) as pale-yellow crystals.

m.p.=112-115° C. (decomposition); ¹H-NMR(DMSO-d₆)δ: 1.78(1.5H, t, J=7.3Hz), 1.90(3H, s), 1.99(1.5H, s), 2.95-3.13(2H, m), 3.25-3.45(4H, m),4.03(1H, q, J=7.3 Hz), 4.25-4.35(6H, m), 6.39(1H, dd, J=2.6, 7.9 Hz),6.78(1H, dd, J=2.6, 7.9 Hz), 7.32(2H, d, J=7.9 Hz), 7.60(2H, d, J=7.9Hz), 7.75(1H, m), 8.47(1H, t, J=5.9 Hz), 11.69(1H, brs); IR(KBr): 3263,2987, 2541, 1666, 1614 cm⁻¹; MS(EI): 342(M⁺); Elemental analysis:Calculated: C; 57.46, H; 6.43, N; 12.76; Found: C; 57.85, H; 6.86, N;12.67.

Example 86 Synthesis ofN-(4-((4-(5-Chloropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-(5-Chloropyridin-2-yl)piperazine

To piperazine (29.0 g) dissolved at 115° C. was added2,5-dichloropyridine (5.1 g) and the mixture was stirred at 140-150° C.for 1 hr. The reaction mixture was poured into a 1N aqueous sodiumhydroxide solution and extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give the title compound (5.0 g) as apale-brown solid.

¹H-NMR(DMSO-d₆)δ: 2.76(4H, t, J=5.3 Hz), 3.38(4H, t, J=5.3 Hz), 6.81(1H,d, J=8.6 Hz), 7.56(1H, dd, J=3.3, 8.6 Hz), 8.09(1H, d, J=2.6 Hz);MS(EI): 197(M⁺).

(2)N-(4-((4-(5-Chloropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5 g),1-(5-chloropyridin-2-yl)piperazine (1.5 g) and potassium carbonate (1.6g) in dimethylformamide (20 ml) was stirred at 70-80° C. for 8.5 hr. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a brown solid (3.1g). The obtained brown solid was crystallized ethyl acetate to give thetitle compound (1.3 g) as pale-yellow crystals,

m.p.=155-156° C.; ¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.35-2.45(4H, m),3.45-3.50(6H, m), 4.23(2H, d, J=5.9 Hz), 6.84(1H, d, J=9.2 Hz),7.19-7.29(4H, m), 7.58(1H, dd, J=2.6, 9.2 Hz), 8.09(1H, d, J=2.6 Hz),8.31(1H, t, J=5.3 Hz); IR(KBr): 3313, 2915, 2815, 1645, 1591 cm⁻¹;MS(EI): 358(M⁺); Elemental analysis: Calculated: C; 63.59, H; 6.45, N;15.61; Found: C; 63.55, H; 6.48, N; 15.48.

Example 87 Synthesis ofN-(4-((4-(Pyrazin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-(Pyrazin-2-yl)piperazine

To piperazine (48.0 g) dissolved at 110° C. was added 2-chloropyrazine(5.0 ml) and the mixture was stirred at 150° C. for 2 hr. The reactionmixture was poured into an aqueous sodium hydroxide solution andextracted with chloroform. The extract was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated togive the title compound (6.4 g) as a brown oil.

¹H-NMR(DMSO-d₆)δ: 2.97-3.01(4H, m), 3.54-3.58(4H, m), 7.84(1H, d, J=2.6Hz), 8.06(1H, dd, J=1.3, 2.6 Hz), 8.13(1H, d, J=1.3 Hz); MS(EI):164(M⁺).

(2) N-(4-((4-(Pyrazin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.6 g),1-(pyrazin-2-yl)piperazine (1.3 g) and potassium carbonate (1.6 g) indimethylformamide (20 ml) was stirred at 70-80° C. for 7 hr. Thereaction mixture was poured into water and extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=20:1) to give a pale-yellow solid (1.8 g). Theobtained pale-yellow solid was crystallized from hexane-ethyl acetate togive the title compound (1.2 g) as pale-yellow crystals, m.p.=118-119°C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.40-2.45(4H, m), 3.49(2H, s),3.50-3.55(4H, m), 4.24(2H, d, J=5.9 Hz), 7.20-7.29(4H, m), 7.82(1H, d,J=2.6 Hz), 8.06(1H, d, J=1.3 Hz), 8.29-8.35(2H, m); IR(KBr): 3307, 2929,2845, 1639, 1578 cm⁻¹; MS(EI): 325(M⁺); Elemental analysis: Calculated:C; 66.44, H; 7.12, N; 21.52; Found: C; 66.49, H; 7.10, N; 21.34.

Example 88 Synthesis ofN-(4-((4-(5-Nitrothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-(5-Nitrothiazol-2-yl)piperazine

To a solution of piperazine (18.2 g) and potassium carbonate (12.6 g) inacetonitrile (150 ml) was added 2-bromo-5-nitrothiazole (14.7 g) at 40°C. and the mixture was stirred at 60° C. for 40 min. The reactionmixture was poured into water and extracted with chloroform. The extractwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated to give a brown solid (11.2 g). The obtainedbrown solid was purified by silica gel column chromatography (developingsolvent; chloroform:methanol=9:1) to give the title compound (4.8 g) asyellow crystals.

¹H-NMR(DMSO-d₆)( δ: 2.80(4H, t, J=5.3 Hz), 3.55(4H, t, J=5.3 Hz),8.37(1H, s); MS(EI): 214(M⁺);

(2)N-(4-((4-(5-Nitrothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (0.5 g),1-(5-nitrothiazol-2-yl) piperazine (0.5 g) and potassium carbonate (0.5g) in dimethylformamide (15 ml) was stirred at 80° C. for 3.5 hr. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a yellow solid (1.5g). The obtained pale-yellow solid was crystallized from ethyl acetateto give the title compound (0.5 g) as yellow crystals, m.p.=151-152° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.40-2.50(4H, m), 3.52(2H, s),3.60-3.70(4H, m), 4.23(2H, d, J=5.9 Hz), 7.23-7.29(4H, m), 8.31(1H, t,J=5.3 Hz), 8.37(1H, s); IR(KBr): 3296, 2964, 1651, 1558, 1504 cm⁻¹;MS(EI): 375(M⁺); Elemental analysis: Calculated: C; 54.38, H; 5.64, N;18.65; Found: C; 54.26, H; 5.65, N; 18.38.

Example 89 Synthesis ofN-(4-((4-(2,6-Dichloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

The roughly purified product (0.9 g) ofN-(4-((4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideobtained in Example 88(3) was crystallized from ethyl acetate to givethe title compound (0.7 g) as white crystals,. m.p.=165-166° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.35-2.45(4H, m), 3.48(2H, s),3.60-3.70(4H, m), 4.23(2H, d, J=5.9 Hz), 6.99(1H, s), 7.19-7.29(4H, m),8.29(1H, t, J=5.9 Hz); IR(KBr): 3249, 2910, 1646, 1598 cm⁻¹; MS(EI):394(M⁺); Elemental analysis: Calculated: C; 54.83, H; 5.37, N; 17.76;Found: C; 54.88, H; 5.41, N; 17.60.

Example 90 Synthesis ofN-(4-((4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide1/2 Hydrate

(1) 1-Acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine

To a solution of 2,4,6-trifluoropyrimidine (2.0 g) and potassiumcarbonate (3.1 g) in acetonitrile (15 ml) was added a solution of1-acetylpiperazine (1.9 g) in acetonitrile (5 ml) over 10 min underice-cooling and the mixture was stirred at room temperature for 1 hr.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine and dried over anhydroussodium sulfate. The solvent was evaporated to give a pale-yellow oil.The obtained pale-yellow oil was purified by silica gel columnchromatography to give the title compound (1.8 g) and1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine (1.7 g) both as awhite solid.

¹H-NMR(CDCl₃)δ: 2.15(3H, s), 3.55-3.65(2H, m), 3.65-3.70(2H, m),3.80-3.90(4H, m), 5.75(1H, t, J=2.0 Hz); MS(EI): 242(M⁺);

(2) 1-(4,6-Dimethoxypyrimidin-2-yl)piperazine

A solution of 1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.7 g)and sodium hydroxide (0.84 g) in methanol (20 ml)—water (10 ml)wasrefluxed under heating for 7.5 hr. The reaction mixture was poured intowater and extracted with chloroform. The extract was washed with brineand dried over anhydrous sodium sulfate. The solvent was evaporated togive a colorless transparent oil (2.5 g). The obtained colorlesstransparent oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=50:1) to give the titlecompound (1.0 g) as a pale-yellow solid.

¹H-NMR(CDCl₃)δ: 2.90(4H, t, J=5.3 Hz), 3.77(4H, t, J=5.3 Hz)., 3.85(6H,s), 5.36(1H, s); IR(KBr): 2985, 2944, 1583, 1564 cm⁻¹; MS(EI): 224(M⁺);Elemental analysis: Calculated: C; 53.55, H; 7.19, N; 24.98; Found: C;53.65, H; 7.24, N; 24.85.

(3)N-(4-((4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide1/2 Hydrate

A solution of N-(4-chloromethylphenylmethyl) acetamide (0.93 g),1-(4,6-dimethoxypyrimidin-2-yl)piperazine (0.94 g) and potassiumcarbonate (0.97 g) in dimethylformamide (10 ml) was stirred at 80° C.for 1.5 hr. The reaction mixture was poured into water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givea brown oil (2.0 g). The obtained brown oil was crystallized from ethylacetate:diisopropyl ether(1:3, 40 ml) to give the title compound (1.3 g)as pale-yellow crystals, m.p.=130-131° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.40-2.50(4H, m), 3.45-3.60(2H, m),3.65-3.75(4H, m), 3.78(6H, s), 4.24(2H, d, J=5.9 Hz), 5.39(1H, s),7.20-7.30(4H, m), 8.32(1H, t, J=5.3 Hz); IR(KBr): 3317, 2829, 1641, 1578cm⁻¹; MS(EI): 385(M⁺) Elemental analysis: Calculated: C; 60.90, H; 7.15,N; 17.75; Found: C; 61.13, H; 6.99, N; 17.75.

Example 91 Synthesis ofN-(4-((4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide(Another Method)

A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (5.0g) obtained in Example 88(2), 2-chloro-4,6-dimethoxypyrimidine (3.9 g)and potassium carbonate (4.2 g) in acetonitrile (50 ml) was refluxedunder heating for 5 hr. The reaction mixture was poured into ice waterand extracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givea pale-brown solid. The obtained pale-brown solid was purified by silicagel column chromatography (developing solvent; chloroform:methanol=9:1)and crystallized from diisopropyl ether to give the title compound (5.0g) as white crystals.

¹H-NMR(DMSO-d6)δ: 1.87(3H, s), 2.40-2.50(4H, m), 3.45-3.60(2H, m),3.65-3.75(4H, m), 3.78(6H, s), 4.24(2H, d, J=5.9 Hz), 5.39(1H, s),7.20-7.30(4H, m), 8.32(1H, t, J=5.3 Hz).

Example 92 Synthesis ofN-(4-((4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide1/2 Hydrate

(1) 1-Acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine

By the manipulation of Example 90(1), the title compound (1.7 g) wasobtained as a white solid.

¹H-NMR(CDCl₃)δ: 2.15(3H, s), 3.55-3.70(4H, m), 3.70-3.85(4H, m),5.95(1H, d, J=2.0 Hz); MS(EI): 242(M⁺).

(2) 1-(2,6-Dimethoxypyrimidin-4-yl)piperazine

A solution of 1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine (1.5 g)and sodium hydroxide (0.8 g) in methanol (10 ml)-water (10 ml) wasrefluxed under heating for 4 hr. The reaction mixture was poured intowater and extracted with chloroform. The extract was washed with brineand dried over anhydrous sodium sulfate. The solvent was evaporated togive a colorless transparent oil (1.8 g). The obtained colorlesstransparent oil was purified by silica gel column chromatography(developing solvent; chloroform:methanol=50:1) to give the titlecompound (1.2 g) as a colorless transparent oil.

¹H-NMR(CDCl₃)δ: 2.90-3.00(4H, m), 3.53-3.57(4H, m), 3.90(3H, s),3.91(3H, s), 5.48(1H, s); MS(EI): 224(M⁺);

(3)N-(4-((4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide1/2 Hydrate

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g),1-(2,6-dimethoxypyrimidin-4-yl)piperazine (1.1 g) and potassiumcarbonate (1.0 g) in dimethylformamide (10 ml) was stirred at 80° C. for2 hr. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated to give abrown oil (2.1 g). The obtained brown oil was purified by silica gelcolumn chromatography (developing solvent; chloroform:methanol=9:1) andcrystallized from ethyl acetate:diisopropyl ether (1:2, 30 ml) to givethe title compound (1.0 g) as white crystals, m.p.=89-90° C.

¹H-NMR(DMSO-d₆)δ: 1.87(3H, s), 2.30-2.40(4H, m), 3.47(2H, s),3.50-3.57(4H, m), 3.77(3H, s), 3.78(3H, s), 4.23(2H, d, J=5.9 Hz),5.70(1H, s), 7.22-7.28(4H, m), 8.29(1H, t, J=5.9 Hz); IR(KBr): 3269,1652, 1608, 1564 cm⁻¹; MS(EI): 385(M⁺); Elemental analysis: Calculated:C; 60.90, H; 7.15, N; 17.75; Found: C; 60.78, H; 7.12, N; 17.67.

Example 93 Synthesis ofN-(4-((4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 2-Chloro-4,6-dimethylpyrimidine

A solution of 2-hydroxy-4,6-dimethylpyrimidine (5.0 g) in phosphorousoxychloride (19 ml) was refluxed under heating for 9 hr. The reactionmixture was added dropwise to an aqueous sodium hydroxide solution andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a yellow oil (3.0 g). The obtained yellow oil waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=30:1) to give the title compound (2.4 g) as apale-yellow oil.

¹H-NMR(CDCl₃)δ: 2.49(6H, s), 6.98(1H, s).

(2)N-(4-((4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.7g) obtained in Example 88(2), 2-chloro-4,6-dimethylpyrimidine (1.0 g)and potassium carbonate (3.0 g) in acetonitrile (50 ml) was refluxedunder heating for 7 hr. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givea yellow oil. The obtained yellow oil was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=20:1) andcrystallized from diisopropyl ether and recrystallized from ethylacetate-hexane to give the title compound (1.1 g) as white crystals.

m.p.=127-128° C.; ¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.27(6H, s), 2.47(4H, t,J=5.3 Hz), 3.52(2H, s), 3.83(4H, t, J=5.3 Hz), 4.42(2H, d, J=5.9 Hz),5.79(1H, brs), 6.25(1H, s), 7.22-7.33(4H, m); IR(KBr): 3301, 1643, 1573cm⁻¹; MS(EI): 353(M⁺); Elemental analysis: Calculated: C; 67.96, H;7.70, N; 19.81; Found: C; 68.03, H; 7.76, N; 19.73.

Example 94 Synthesis ofN-(1-Methyl-1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(thiazol-2-yl)piperazineinstead of phenylpiperazine, the title compound was obtained aspale-yellow crystals, m.p.=118-120° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.56(4H, t, J=5.3 Hz),3.49(4H, t, J=5.3 Hz), 3.52(2H, s), 5.72(1H, br.s), 6.55(1H, d, J=3.3Hz), 7.19(1H, d, J=4.0 Hz), 7.26-7.36(4H, m). MS(FAB): 359(M⁺);Elemental analysis: Calculated: C; 63.66, H; 7.31, N; 15.63; Found: C;63.70, H; 7.34, N; 15.65.

Example 95 Synthesis ofN-(1-Methyl-1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) Synthesis of 4-(1-Acetamide-1-methylethyl)benzoic Acid

To a solution of sodium hydroxide (164.2 g) in water (500 ml) was addeddropwise bromine (70 ml) over 30 min under ice-cooling. To this solutionwas added dropwise a solution of N-(1-(4-acetylphenyl)-1-methylethyl)acetamide (100 g) in dioxane (1000 ml) over 1 hr and the mixture wasstirred at 10° C. for 30 min. To the reaction mixture was added asolution of sodium sulfite (19 g) in water (2000 ml) and stirred.Thereto was added hydrochloric acid and the resulting crystals werecollected by filtration to give the title compound (73.4 g) aspale-brown crystals, m.p.=235-237° C.

¹H-NMR(DMSO-d₆)δ: 1.54(6H, s), 1.83(3H, s), 7.42(2H, d, J=8.6 Hz),7.86(2H, d, J=8.6 Hz), 8.14(1H, s), 12.72(1H, br.s). MS(EI): 221(M⁺).

(2) Synthesis of Methyl 4-(1-Acetamido-1-methylethyl)benzoate

A suspension of 4-(1-acetamido-1-methylethyl)benzoic acid (73.4 g) andsulfuric acid (0.7 ml) in methanol (370 ml) was refluxed for 16 hr. Thesolvent was evaporated and 10% aqueous sodium hydrogencarbonate (500 ml)was added and the mixture was extracted with ethyl acetate (500 ml). Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the obtained residuewas recrystallized from ethyl acetate-isopropyl ether to give the titlecompound (39.0 g) as pale-yellow crystals, m.p.=165-167° C.

¹H-NMR(DMSO-d₆)δ: 1.53(6H, s), 1.83(3H, s), 3.83(3H, s), 7.44(2H, d,J=8.6 Hz), 7.87(2H, d, J=8.6 Hz), 8.15(1H, s). MS(EI): 235(M⁺).

(3) Synthesis of N-(1-(4-Hydroxymethylphenyl)-1-methylethyl)acetamide

To a solution of methyl 4-(1-acetamido-1-methylethyl)benzoate (37.14g)in tetrahydrofuran (370 ml) was added lithium borohydride (6.88 g) andthe mixture was refluxed for 19 hr. The reaction mixture was poured intowater (1000 ml) and extracted with ethyl acetate (1000 ml). The extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the obtained residue wasrecrystallized from ethyl acetate to give the title compound (18.24m.p.=126-129° C.

¹H-NMR(DMSO-d₆)δ: 1.52(6H, s), 1.81(3H, s), 4.44(2H, d, J=5.3 Hz),5.06(1H, t, J=5.3 Hz), 7.18-7.27(4H, m), 7.98(1H, br.s). MS(EI):207(M⁺).

(4) Synthesis of N-(1-(4-Chloromethylphenyl)-1-methylethyl)acetamide

To a solution of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide(18.24 g) in chloroform (180 ml) was added dropwise thionyl chloride(7.07 ml) over 10 min under ice-cooling and the mixture was stirred atroom temperature for 20 hr. The reaction mixture was poured into water(1000 ml) and the organic layer was separated. The organic layer waswashed with aqueous sodium hydrogencarbonate and saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the title compound (19.17 g) as pale-yellow crystals, m.p.=124-125°C.

¹H-NMR(DMSO-d₆)δ:1.52(6H, s), 1.82(3H, s), 4.71(2H, s), 7.28-7.35(4H,m), 8.05(1H, s). MS(EI): 225(M⁺).

(5) Synthesis ofN-(1-Methyl-1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=137-138° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.96(3H, s), 2.50(4H, t, J=5.3 Hz),3.51(2H, s), 3.82(4H, t, J=5.3 Hz), 5.76(1H, br.s), 6.46(1H, t, J=4.6Hz), 7.28-7.36(4H, m), 8.29(2H, t, J=4.6 Hz). MS(EI): 353(M⁺). Elementalanalysis: Calculated: C; 67.96, H; 7.70, N; 19.81; Found: C; 67.94, H;7.65, N; 19.80.

Example 96 Synthesis ofN-(1-(4-((4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(4,6-dimethoxypyrimidin-2-yl)piperazine obtained in Example 90(2)instead of phenylpiperazine, the title compound was obtained as whitecrystals, m.p.=199-202° C.

¹H-NMR(DMSO-d₆)δ: 1.53(6H, s), 1.82(3H, s), 2.38-2.41(4H, m), 3.46(2H,s), 3.71(4H, m), 3.78(6H, s), 5.38(1H, s), 7.20-7.28(4H, m), 7.99(1H,s); MS(FAB): 414(M⁺); Elemental analysis: Calculated: C; 63.90, H; 7.56,N; 16.94; Found: C; 63.73, H; 7.64, N; 16.82.

Example 97 Synthesis ofN-(4-((4-(2-Chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamideandN-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

To a suspension of N-(4-((piperazin-1-yl)methyl)-phenylmethyl)acetamide(1.0 g) obtained in Example 78(2) and 2,4-dichloropyrimidine (0.60 g) inacetonitrile (20 ml) was added potassium carbonate (0.84 9) and themixture was stirred at room temperature for 2 hr. The reaction mixturewas poured into water (200 ml) and extracted with ethyl acetate (100ml). The extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the obtainedresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:methanol=20:1-10:1) to giveN-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide(0.61 g) as white crystals andN-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide(10 mg) as white crystals.N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide.

m.p.=132-133° C.; ¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.49(4H, t, J=5.3 Hz),3.52(2H, s), 3.65(4H, br.), 4.42(2H, d, J=5.9 Hz), 5.96(1H, br.s),6.36(1H, d, J=6.6 Hz), 7.23-7.31(4H, m), 8.00(1H, d, J=6.6 Hz). MS(FAB):360(M⁺); Elemental analysis: Calculated: C; 60.08, H; 6.16, N; 19.46;Found: C; 60.08, H; 6.11, N; 19.43.

N-(4-((4-(4-Chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

m.p.=122-124° C.; ¹H-NMR(CDCl₃)δ: 2.01(3H, s), 2.47(4H, t, J=5.3 Hz),3.52(2H, s), 3.80-3.83(4H,t), 4.41(2H, d, J=5.3 Hz), 5.99(1H, br.s),6.48(1H, d, J=4.6 Hz), 7.22-7.32(4H, m), 8.13(1H, d, J=5.3 Hz). MS(FAB):360(M⁺).

Example 98 Synthesis ofN-(1-((4-(4-Methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Synthesis of 2-Chloro-4-methoxypyrimidine

To a solution of 2,4-dichloropyrimidine (32.4 g) in methanol (200 ml)was added dropwise a solution of sodium methoxide (11.7 g) in methanol(120 ml) over 40 min and the mixture was stirred for 30 min. Thereaction mixture was poured into water (500 ml) and extracted withchloroform (300 ml). The extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe obtained residue was recrystallized from hexane to give the titlecompound (21.5 g) as white crystals, m.p.=50-52° C.

¹H-NMR(CDCl₃)δ: 4.02(3H, s), 6.68(1H, d, J=5.3 Hz), 8.29(1H, d, J=5.3Hz). MS(EI): 144(M⁺).

(2) Synthesis of 1-(4-Methoxypyrimidin-2-yl)piperazine

A suspension of 2-chloro-4-methoxypyrimidine (21.5 g) and piperazine(64.0 g) in acetonitrile (200 ml) was refluxed for 30 min. The reactionmixture was poured into water (500 ml) and extracted with chloroform(400 ml). The extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated to give thetitle compound (26.0 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 2.94(4H, m), 3.76-3.80(4H, m), 3.88(3H, s), 5.97(1H, d,J=5.9 Hz), 8.05(1H, d, J=5.3 Hz). MS(EI): 194(M⁺).

(3) Synthesis ofN-(1-((4-(4-Methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(4-methoxypyrimidin-2-yl)piperazine instead of phenylpiperazine, thetitle compound was obtained as white crystals, m.p.=144-145° C.

1H-NMR(CDCl₃)δ: 2.02(3H, s), 2.46-2.50(4H, m), 3.53(2H, s),3.79-3.82(4H, m), 3.86(3H, s), 4.42(2H, d, J=5.3 Hz), 5.84(1H, br.s),5.96(1H, d, J=5.9 Hz), 7.23-7.33(4H, m), 8.03(1H, d, J=5.3 Hz). MS(EI):355(M⁺); Elemental analysis: Calculated: C; 64.21, H; 7.09, N; 19.70;Found: C; 63.98, H; 6.93, N; 19.60.

Example 99 Synthesis ofN-(4-((4-(4-(N,N-Dimethylamino)pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) Synthesis of 2-Chloro-4-(N,N-dimethylamino)pyrimidine

To a 20% dimethylamine-ethanol solution (15.4 g) of2,4-dichloropyrimidine (3.0 g) was added triethylamine (3 ml) underice-cooling, and the mixture was stirred for 30 min. The reactionmixture was poured into water (100 ml) and extracted with ethyl acetate(100 ml). The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated and the obtainedresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:hexane=1:1) to give the title compound (1.90 g)as white crystals, m.p.=77-79° C.

¹H-NMR(CDCl₃)δ: 3.11(6H, s), 6.31(1H, d, J=5.9 Hz), 8.00(1H, d, J=5.9Hz). MS(EI): 157(M⁺).

(2) Synthesis ofN-(4-((4-(4-(N,N-Dimethylamino)pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide obtained in Example78(2) instead of N-(4-chloromethylphenylmethyl)acetamide and2-chloro-4-(N,N-dimethylamino)pyrimidine instead of phenylpiperazine,the title compound was obtained as white crystals, m.p.=152-155° C.

¹H-NMR(CDCl₃)δ: 1.99(3H, s), 2.44-2.48(4H, m), 3.02(6H, s), 3.51(2H, s),3.75-3.78(4H, m), 4.40(2H, d, J=5.3 Hz), 5.77(1H, d, J=5.9 Hz), 6.08(1H,br.s), 7.21-7.32(4H, m), 7.88(1H, d, J=5.9 Hz). MS(EI): 368(M⁺);Elemental analysis: Calculated: C; 65.19, H; 7.66, N; 22.81; Found: C;64.84, H; 7.59, N; 22.53.

Example 100 Synthesis ofN-(1-(4-((4-(Thiazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead ofphenylpiperazine, the title compound was obtained as pale-yellowcrystals, m.p.=184-185° C.

¹H-NMR(CDCl₃)δ: 1.26 and 1.36(4H, s and d, J=4.0 Hz), 1.99(3H, s),2.51-2.57(4H, m), 3.46-3.53(6H, m), 6.21(1H, br), 6.54-6.56(1H, m),7.09-7.31(5H, m). MS(EI): 356(M⁺); Elemental analysis: Calculated: C;64.02, H; 6.79, N; 15.72; Found: C; 63.83, H; 6.55, N; 15.58.

Example 101 Synthesis ofN-(1-(4-((4-(Thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3)instead of N-(4-chloromethylphenylmethyl)acetamide and1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead ofphenylpiperazine, the title compound was obtained as white crystals,m.p.=136-137° C.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=7.3 Hz), 1.98(3H, s), 2.55(4H, t, J=5.3Hz), 3.49(4H, t, J=5.3 Hz), 3.53(2H, s), 5.12(1H, dt, J=7.3 Hz),5.74-5.77(1H, br), 6.56(1H, d, J=3.3 Hz), 7.18(1H, d, J=3.3 Hz),7.25-7.33(4H, m). MS(EI): 344(M⁺); Elemental analysis: Calculated: C;62.76, H; 7.02, N; 16.26; Found: C; 62.74, H; 6.92, N; 16.21.

Example 102 Synthesis ofN-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3)instead of N-(4-chloromethylphenylmethyl)acetamide and1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine, the title compound was obtained as white crystals,m.p.=109-111° C.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=7.3 Hz), 1.98(3H, s), 2.50-2.53(4H, m),3.51-3.55(6H, m), 5.13(1H, dq, J=7.3 Hz), 5.73-5.75(1H, br),6.13-6.17(1H, m), 6.37-6.41(1H, m), 7.26-7.33(4H, m), 7.46-7.55(1H, m).MS(EI): 356(M⁺); Elemental analysis: Calculated: C; 67.39, H; 7.07, N;15.72; Found: C; 67.29, H; 7.00, N; 15.76.

Example 103 Synthesis of N-(1-(4-((4-(6-Fluoropyridin-2-5yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine, the title compound was obtained as white crystals,m.p.=133-134° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.50-2.54(4H, m),3.51-3.55(6H, m), 5.71(1H, br.s), 6.13-6.16(1H, m), 6.36-6.41(1H, m),7.26-7.36(4H, m), 7.46-7.55(1H, m). MS(EI): 370(M⁺); Elemental analysis:Calculated: C; 68.08, H; 7.35, N; 15.12; Found: C; 68.10, H; 7.15, N;15.14.

Example 104 Synthesis ofN-(1-(4-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3)instead of N-(4-chloromethylphenylmethyl)acetamide and1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compoundwas obtained as pale-yellow crystals, m.p.=120-121° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.50-2.54(4H, m),3.51-3.55(6H, m), 5.71(1H, br), 6.13-6.16(1H, m), 6.36-6.41(1H, m),7.26-7.36(4H, m), 7.46-7.55(1H, m). MS(EI): 338(M⁺); Elemental analysis:Calculated: C; 70.98, H; 7.74, N; 16.55; Found: C; 70.91, H; 7.70, N;16.51.

Example 105 Synthesis ofN-(1-Methyl-1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compoundwas obtained as white crystals, m.p.=129-130° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.53-2.57(4H, m),3.52-3.55(6H, m), 5.71(1H, br.s), 6.58-6.64(2H, m), 7.26-7.36(4H, m),7.42-7.49(1H, m), 8.17-8.18(1H, m). MS(EI): 352(M⁺); Elemental analysis:Calculated: C; 71.56, H; 8.01, N; 15.90; Found: C; 71.59, H; 7.93, N;15.88.

Example 106 Synthesis ofN-(1-(4-((4-(4-Methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) insteadof phenylpiperazine, the title compound was obtained as white crystals,m.p.=160-162° C.

¹H-NMR(CDCl₃)δ: 1.70(6H, s), 1.97(3H, s), 2.47-2.51(4H, m), 3.52(2H, s),3.79-3.83(4H, m), 3.87(3H, s), 5.71(1H, br), 5.96(1H, d, J=5.3 Hz),7.26-7.36(4H, m), 8.04(1H, d, J=5.3 Hz). MS(EI): 383(M⁺); Elementalanalysis: Calculated: C; 65.77, H; 7.62, N; 18.26; Found: C; 65.69, H;7.46, N; 18.37.

Example 107 Synthesis ofN-(1-(4-((4-(4-Methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3)instead of N-(4-chloromethylphenylmethyl)acetamide and1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) insteadof phenylpiperazine, the title compound was obtained as pale-yellowcrystals, m.p.=113-115° C.

¹H-NMR(CDCl₃)δ: 1.49(3H, d, J=7.3 Hz), 1.98(3H, s), 2.46-2.50(4H, m),3.52(2H, s), 3.79-3.83(4H, m), 3.86(3H, s), 5.13(1H, dq, J=7.3 Hz),5.70-5.72(1H, br), 5.96(1H, d, J=5.3 Hz), 7.26-7.34(4H, m), 8.03(1H, d,J=5.9 Hz). MS(EI): 369(M⁺); Elemental analysis: Calculated: C; 65.02, H;7.37, N; 18.96; Found: C; 64.90, H; 7.15, N; 19.21.

Example 108 Synthesis ofN-(4-((4-(4,6-Diethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-Acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine

A solution of 1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.5 g)and sodium ethoxide (1.3 g) in ethanol (15 ml) was refluxed underheating for 1 hr. The reaction mixture was poured into ice water andextracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givethe title compound (1.8 g) as a pale-brown solid.

¹H-NMR(CDCl₃)δ: 1.36(6H, t, J=7.3 Hz), 2.14(3H, s), 3.48-3.52(2H, m),3.64-3.68(2H, m), 3.73-3.83(4H, m), 4.27(4H, q, J=7.3 Hz), 5.38(1H, s);MS(EI): 294(M⁺).

(2) 1-(4,6-Diethoxypyrimidin-2-yl)piperazine

A solution of 1-acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine (1.8 g)and sodium hydroxide (1.0 g) in ethanol (10 ml)—water (10 ml) wasrefluxed under heating for 11 hr. The reaction mixture was poured intowater and extracted with chloroform. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated to give thetitle compound (1.6 g) as a pale-brown oil.

¹H-NMR(CDCl₃)δ: 1.35(6H, t, J=7.3 Hz), 2.89(4H, t, J=5.3 Hz), 3.74(4H,t, J=5.3 Hz), 4.26(4H, q, J=7.3 Hz), 5.32(1H, s) MS(EI): 252(M⁺).

(3)N-(4-((4-(4,6-Diethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (1.2 g),1-(4,6-diethoxypyrimidin-2-yl)piperazine (1.7 g) and potassium carbonate(1.3 g) in dimethylformamide (20 ml) was stirred at 80° C. for 4.5 hr.The reaction mixture was poured into water(150 ml) and extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated to give abrown oil (2.9 g). The obtained brown oil was purified by silica gelcolumn chromatography to give a pale-yellow oil (2.4 g). The obtainedpale-yellow oil was crystallized from ethyl acetate/hexane (2:1, 30 ml)to give the title compound (1.7 g) as white crystals, m.p.=119-120° C.

¹H-NMR(CDCl₃)δ: 1.34(6H, t, J=7.3 Hz), 2.03(3H, s), 2.45(4H, t, J=5.3Hz), 3.52(2H, s), 3.77(4H, t, J=5.3 Hz), 4.25(4H, q, J=7.3 Hz), 4.42(4H,d, J=5.9 Hz), 5.32(1H, s), 5.71(1H, brs), 7.22-7.33(4H, m); IR(KBr):3288, 2977, 1643, 1578 cm⁻¹; MS(EI): 413(M⁺); Elemental analysis:Calculated: C; 63.90, H; 7.56, N; 16.94; Found: C; 63.81, H; 7.47, N;16.72.

Example 109 Synthesis ofN-(4-((4-(4,6-bis(Dimethylamino)-pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine

1-Acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.9 g) was dissolvedin 12% dimethylamine-ethanol solution (30 ml) and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure. Water was added to the residue andthe mixture was extracted with ethyl acetate. The extract was washedwith brine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give the title compound (2.1 g) as a yellow solid.

¹H-NMR(CDCl₃)δ: 2.13(3H, s), 3.06(6H, s), 3.47-3.51(2H, m),3.64-3.68(2H, m), 3.74-3.81(4H, m), 5.33(1H, d, J=1.3 Hz); MS(EI):267(M⁺).

(2) 1-Acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine

1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g)was dissolved in 12% dimethylamine-ethanol solution (30 ml) in anautoclave, and the mixture was stirred at 100° C. for 5 hr. The reactionmixture was concentrated under reduced pressure and chloroform was addedto the reside. The chloroform solution was washed with brine and driedover anhydrous sodium sulfate. The solvent was evaporated to give thetitle compound (1.3 g) as a pale-yellow solid.

¹H-NMR(CDCl₃)δ: 2.13(3H, s), 3.02(12H, s), 3.48-3.52(2H, m),3.65-3.68(2H, m), 3.73-3.82(4H, m), 4.91(1H, s); MS(EI): 292(M⁺).

(3) 1-(4,6-bis(Dimethylamino)pyrimidin-2-yl)piperazine

A solution of1-acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (1.3 g) andsodium hydroxide (0.5 g) in ethanol (15 ml)—water (15 ml) was refluxedunder heating for 9.5 hr. The reaction mixture was concentrated underreduced pressure, and ethyl acetate was added to the residue and themixture was washed with brine. The organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated to give thetitle compound (0.9 g) as a pale-brown oil.

¹H-NMR(CDCl₃)δ: 1.73(1H, s), 2.87-2.89(4H, m), 3.01(12H, s),3.70-3.74(4H, m), 4.89(1H, s); MS(EI): 250(M⁺).

(4) N-(4-((4-(4,6-bis(Dimethylamino)pyrimidin-2-yl)piperazin-1-ylmethyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (0.7 g),1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (0.9 g) and potassiumcarbonate (0.7 g) in dimethylformamide (10 ml) was stirred at 80° C. for6 hr. The reaction mixture was poured into water (100 ml) and extractedwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated to givea brown solid (1.6 g). The obtained brown solid was crystallized fromethyl acetate/ethanol (2:1, 30 ml) to give the title compound (0.9 g) aspale-yellow crystals.

m.p.=189-190° C. (decomposition); ¹H-NMR(CDCl₃)(δ: 2.00(3H, s),2.43-2.47(4H, m), 2.99(12H, s), 3.51(2H, s), 3.74-3.77(4H, m), 4.40(2H,d, J=5.3 Hz), 4.88(1H, s), 5.80(1H, brs), 7.21-7.32(4H, m); IR(KBr):3291, 2935, 2819, 1645, 1578 cm⁻¹; MS(EI): 411(M⁺); Elemental analysis:Calculated: C; 64.21, H; 8.08, N; 23.82; Found: C; 63.81, H; 7.79, N;22.96.

Example 110 Synthesis ofN-(4-((4-(4-Dimethylamino-6-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 1-(4-Dimethylamino-6-methoxypyrimidin-2-yl)piperazine

1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g)obtained in Example 109(1) and sodium methoxide (1.1 g) were refluxedunder heating in methanol (10 ml) for 28 hr. The reaction mixture waspoured into water (100 ml) and extracted with chloroform. The extractwas dried over anhydrous sodium sulfate and the solvent was evaporatedto give the title compound (1.1 g) as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 2.88-2.92(4H, m), 3.01(6H, s), 3.72-3.76(4H, m),3.84(3H, s), 5.15(1H, s); MS(EI): 237(M⁺).

(2)N-(4-((4-(4-Dimethylamino-6-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9 g),1-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazine (1.1 g) andpotassium carbonate (1.0 g) in dimethylformamide (10 ml) was stirred at80° C. for 8.5 hr. The reaction mixture was poured into water (100 ml)and extracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a brown oil (1.9 g). The obtained brown oil waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=9:1) to give a yellow oil (1.6 g). The obtainedyellow oil was crystallized from ethyl acetate/hexane (1:1, 20 ml) togive the title compound (1.0 g) as pale-yellow crystals.

m.p.=115-118° C.; ¹H-NMR(CDCl₃)δ: 2.01(3H, s), 2.43-2.47(4H, m),2.99(6H, s), 3.52(2H, s), 3.75-3.79(4H, m), 3.81(3H, s), 4.40(2H, d,J=5.9 Hz), 5.14(1H, s), 5.86(1H, brs), 7.21-7.32(4H, m); IR(KBr): 3261,2939, 2834, 1635, 1589 cm⁻¹; MS(EI): 398(M⁺); Elemental analysis:Calculated: C; 63.29, H; 7.59, N; 21.09; Found: C; 63.38, H; 7.45, N;20.64.

Example 111 Synthesis ofN-(4-((4-(5-Bromothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 4-Acetyl-1-(thiazol-2-yl)piperazine

A solution of 1-(thiazol-2-yl)piperazine (6.7 g) obtained by similarmanipulation to that in Example 81(1), acetic anhydride (5.6 ml) andsodium hydroxide (2.4 g) in water (50 ml)—ethyl acetate (50 ml) wasstirred under ice-cooling for 1 hr. The reaction mixture was extractedwith ethyl acetate and dried over anhydrous sodium sulfate. The solventwas evaporated to give a pale-yellow solid (6.9 g). The obtainedpale-yellow solid was crystallized from ethyl acetate-hexane (1:1, 100ml) to give the title compound (5.0 g) as white crystals.

¹H-NMR(CDCl₃)δ: 2.14(3H, s), 3.44-3.48(2H, m), 3.55-3.62(4H, m),3.74-3.78(2H, m), 6.62(1H, d, J=3.3 Hz), 7.21(1H, d, J=3.3 Hz) MS(EI):211(M⁺).

(2) 4-Acetyl-1-(5-bromothiazol-2-yl)piperazine

A solution of 4-acetyl-1-(thiazol-2-yl)piperazine (3.1 g) andN-bromosuccinimide (2.9 g) in acetic acid (14 ml) was stirred at roomtemperature for 1 hr. The reaction mixture was neutralized with 1Naqueous sodium hydroxide solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated to give a pale-brown solid (2.9 g).The obtained pale-brown solid was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=20:1) to givethe title compound (2.1 g) as a pale-brown solid.

¹H-NMR(CDCl₃)δ: 2.14(3H, s), 3.37-3.41(2H, m), 3.48-3.51(2H, m),3.56-3.60(2H, m), 3.72-3.76(2H, m), 7.09(1H, s); MS(EI): 291((M+1)+).

(3) 1-(5-Bromothiazol-2-yl)piperazine

4-Acetyl-1-(5-bromothiazol-2-yl)piperazine (2.0 g) was dissolved in 6Nhydrochloric acid and refluxed under heating for 4.5 hr. The reactionmixture was neutralized with 1N aqueous sodium hydroxide solution andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give a brown oil (1.5 g). The obtained brown oil waspurified by silica gel column chromatography (developing solvent;chloroform:methanol=9:1) to give the title compound (1.1 g) as apale-yellow solid.

¹H-NMR(CDCl₃)δ: 2.95-2.98(4H, m), 3.37-3.41(4H, m), 7.06(1H, s); MS(EI):248((M+1)+).

(4)N-(4-((4-(5-Bromothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9 g),1-(5-bromothiazol-2-yl)piperazine (1.1 g) and potassium carbonate (0.9g) in dimethylformamide (10 ml) was stirred at 70° C. for 9 hr. Water(100 ml) was poured into the reaction mixture to allow precipitation ofcrystals. The crystals were collected by filtration and washed withwater to give the title compound (1.5 g) as yellow crystals,m.p.=160-163° C.

¹H-NMR(CDCl₃)δ: 2.01(3H, s), 2.50-2.54(4H, m), 3.40-3.44(4H, m),3.52(2H, s), 4.41(2H, d, J=5.3 Hz), 5.91(1H, brs), 7.05(1H, s),7.22-7.31(4H, m); IR(KBr): 3309, 2935, 2821, 1645, 1529 cm⁻¹; MS(EI):410((M+1)+); Elemental analysis: Calculated: C; 49.88, H; 5.17, N;13.69; Found: C; 49.94, H; 5.13, N; 13.54.

Example 112 Synthesis of N-(4-((4-(5-Chlorothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

(1) 4-Acetyl-1-(5-chlorothiazol-2-yl)piperazine

By similar reaction and treatment to that in Example 111(2) usingN-chlorosuccinimide instead of N-bromosuccinimide, the title compoundwas obtained as pale-yellow crystals.

¹H-NMR(CDCl₃)δ: 2.14(3H, s), 3.36-3.40(2H, m), 3.47-3.50(2H, m),3.57-3.60(2H, m), 3.72-3.76(2H, m), 7.00(1H, s); MS(EI): 245(M⁺).

(2) 1-(5-Chlorothiazol-2-yl)piperazine

By similar reaction and treatment to that in Example 111(3) using4-acetyl-1-(5-chlorothiazol-2-yl)piperazine instead of4-acetyl-1-(5-bromothiazol-2-yl)piperazine, the title compound wasobtained as a pale-brown oil.

¹H-NMR(CDCl₃)δ: 2.95-2.98(4H, m), 3.36-3.40(4H, m), 6.98(1H, s) MS(EI):203(M⁺).

(3)N-(4-((4-(5-Chlorothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 111(4) using1-(5-chlorothiazol-2-yl)piperazine instead of1-(5-bromothiazol-2-yl)piperazine, the title compound was obtained aspale-brown crystals, m.p.=142-145° C. (decomposition).

¹H-NMR(CDCl₃)δ: 2.02(3H, s), 2.51-2.54(4H, m), 3.39-3.43(4H, m),3.53(2H, s), 4.41(2H, d, J=5.3 Hz), 5.88(1H, brs), 6.96(1H, s),7.22-7.31(4H, m); MS(EI): 364(M⁺); Elemental analysis: Calculated: C;55.96, H; 5.80, N; 15.35; Found: C; 55.81, H; 5.68, N; 15.38.

Example 113 Synthesis ofN-(4-(1-(4-(Pyrimidin-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamideDihydrochloride 1/2 Hydrate

By similar reaction and treatment to that in Example 1(5) using1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazineand N-(4-(1-chloroethyl)phenylmethyl)acetamide instead ofN-(4-chloromethylphenylmethyl) acetamide, the title compound wasobtained as a yellow amorphous solid.

¹H-NMR(DMSO-d₆)δ: 1.72(3H, d, J=6.6 Hz), 1.89(3H, s), 2.75-3.15(3H, m),3.30-3.90(3H, m), 4.27(2H, d, J=5.3 Hz), 4.45(1H, m), 4.66(2H, m),6.76(1H, t, J=4.9 Hz), 7.33(2H, d, J=7.9 Hz), 7.63(2H, d, J=7.9 Hz),8.44(2H, d, J=4.6 Hz), 8.47(1H, t, J=4.6 Hz). IR(KBr): 3244, 2920, 1659,1626 cm⁻¹; Elemental analysis: Calculated: C; 54.16, H; 6.70, N; 16.62;Found: C; 53.92, H; 7.01, N; 16.39.

Example 114 Synthesis ofN-(1-(4-(1-(4-(Pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazineand N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound was obtainedas a white amorphous solid.

¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.53(6H, s), 1.83(3H, s),2.25-2.50(4H, m), 3.69(4H, m), 6.58(1H, t, J=4.6 Hz), 7.21(2H, d, J=8.6Hz), 7.26(2H, d, J=7.9 Hz), 7.97(1H, s), 7.32(2H, s,J=5.3 Hz); IR(KBr):3331, 2976, 1657, 1585 cm⁻¹; MS(EI): 367(M⁺); Elemental analysis:Calculated: C; 68.63, H; 7.95, N; 19.06; Found: C; 68.23, H; 7.68, N;18.82.

Example 115 Synthesis ofN-(4-(1-(4-(Thiazol-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide 1/2Ethanol 1/2 Hydrate

By similar reaction and treatment to that in Example 1(5) using1-(2-thiazolyl)piperazine instead of phenylpiperazine andN-(4-(1-chloroethyl)phenylmethyl)acetamide instead ofN-(4-chloromethylphenylmethyl) acetamide, the title compound wasobtained as a brown oil.

¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.87(3H, s), 2.38-2.50(4H, m),3.37(4H, m), 3.45(1H, q, J=6.6 Hz), 4.23(2H, d, J=5.9 Hz), 6.81(2H, d,J=3.3 Hz), 7.13(2H, d, J=3.3 Hz), 7.20(2H, d, J=8.6 Hz), 7.27(2H, d,J=7.9 Hz), 8.29(1H, t, J=5.3 Hz). IR(neat): 3284, 2816, 1653 cm⁻¹;MS(EI): 344(M⁺); Elemental analysis: Calculated: C; 60.61, H; 7.50, N;14.88; Found: C; 60.61, H; 7.15, N; 14.98.

Example 116 Synthesis ofN-(1-(4-(1-(4-(Pyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide1/4 Ethanol

By similar reaction and treatment to that in Example 1(5) using1-(2-pyridyl)piperazine instead of phenylpiperazine andN-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl) acetamide, the title compound wasobtained as white crystals.

¹H-NMR(DMSO-d₆)δ: 1.30(3H, d, J=6.6 Hz), 1.53(6H, s), 1.83(3H, s),2.30-2.60(4H, m), 3.37(1H, m), 3.43(4H, m), 6.60(1H, d, J=4.6, 6.6 Hz),6.75(1H, d, J=8.6 Hz), 7.22(2H, d, J=8.6 Hz), 7.27(2H, d, J=8.6 Hz),7.49(1H, m), 7.98(1H, s), 8.09(1H, m); IR(KBr): 3329, 3066, 1659, 1594cm⁻¹; MS(EI): 366(M⁺); Elemental analysis: Calculated: C; 71.49, H;8.37, N; 14.91; Found: C; 71.89, H; 8.07, N; 14.69.

Example 117 Synthesis ofN-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine, the title compound was obtained as white crystals,m.p.=135-136° C.

¹H-NMR(CDCl₃)δ: 1.26 and 1.36(4H, s and d,J=4.6 Hz), 1.99(3H, s),2.48-2.53(4H, m), 3.49-3.55(6H, m), 6.12-6.17(2H, m), 6.36-6.40(1H, m),7.10-7.31(4H, m), 7.45-7.55(1H, m). MS(EI): 368(M⁺); Elemental analysis:Calculated: C; 68.46, H; 6.84, N; 15.21; Found: C; 68.51, H; 6.92, N;15.18.

Example 118 Synthesis ofN-(1-(4-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

By similar reaction and treatment to that in Example 1(5) usingN-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compoundwas obtained as white crystals, m.p.=145-147° C.

¹H-NMR(CDCl₃)δ: 1.26 and 1.36(4H, s and d, J=5.3 Hz), 2.00(3H, s),2.51-2.56(4H, m), 3.50-3.56(6H, m), 6.13(1H, br), 6.58-6.64(1H, m),7.10-7.32(4H, m), 7.42-7.49(1H, m), 8.16-8.19(1H, m). MS(EI): 350(M⁺);Elemental analysis: Calculated: C; 71.97, H; 7.48, N; 15.99; Found: C;72.10, H; 7.52, N; 15.94.

Example 119: Synthesis of(S)-N-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) Synthesis of (S)-N-(1-Phenylethyl)acetamide

To a solution of (S)-(−)-1-phenylethylamine (121 g) and triethylamine(168 ml) in dichloroethane (1200 ml) was added dropwise acetyl chloride(78.2 ml) over 1 hr under ice-cooling and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was poured into water(1000 ml) and the organic layer was separated. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated to give the title compound (143.4 g) aspale-yellow crystals, m.p.=99-101° C.

¹H-NMR(CDCl₃)δ: 1.44(3H, d, J=6.6 Hz), 1.92(3H, s), 5.08(1H, dq, J=7.3Hz), 6.37(1H, br), 7.20-7.34(5H, m). MS(EI): 163(M⁺).

(2) Synthesis of (S)-N-(1-(4-Acetylphenyl)ethyl)acetamide

To a solution of (S)-1-phenylethylacetamide (143.4 g) and acetylchloride (93.7 ml) in dichloroethane (700 ml) was added aluminumchloride (257.7 g) over 30 min under ice-cooling. The mixture wasstirred at 10° C. for 30 min and at 60° C. for 3 hr. The reactionmixture was poured into icewater (1500ml) and the organic layer wasseparated. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theobtained residue was purified by silica gel column chromatography(developing solvent; ethyl acetate) and recrystallized from ethylacetate-hexane to give the title compound (76.4 g) as white crystals,m.p.=125-128° C.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 2.00(3H, s), 2.58(3H, s),5.15(1H, dq, J=7.3 Hz), 5.98(1H, br.d, J=6.6 Hz), 7.40(2H, d, J=8.6 Hz),7.92(2H, d, J=7.9 Hz). MS(EI): 205(M⁺).

(3) Synthesis of (S)-4-(1-Acetamidoethyl)benzoic Acid

By similar reaction and treatment to that in Example 95(1) using(S)-N-(1-(4-acetylphenyl)ethyl)acetamide instead ofN-(1-(4-acetylphenyl)-1-methylethyl) acetamide, the title compound wasobtained as yellow crystals, m.p.=186-190° C.

¹H-NMR(DMSO-d₆)δ: 1.35(3H, d, J=7.3 Hz), 1.86(3H, s), 4.96(1H, dq, J=7.3Hz), 7.42(2H, d, J=8.6 Hz), 7.91(2H, d, J=7.9 Hz), 8.36(1H, d, J=7.9Hz), 12.87(1H, br.s). MS(EI): 207(M⁺).

(4) Synthesis of Methyl (S)-4-(1-Acetamidoethyl)benzoate

By similar reaction and treatment to that in Example 95(2) using(S)-4-(1-acetamidoethyl)benzoic acid instead of4-(1-acetamido-1-methylethyl)benzoic acid, the title compound wasobtained as white crystals.

m.p.=125-127° C.; ¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=7.3 Hz), 2.00(3H, s),3.91(3H, s), 5.16(1H, dq, J=7.3 Hz), 5.85-5.87(1H, br), 7.36-7.39(2H,m), 7.98-8.01(2H, m). MS(EI): 221(M⁺).

(5) Synthesis of (S)-N-(1-(4-Hydroxymethylphenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(3) using methyl(S)-4-(1-acetamidoethyl)benzoate instead of methyl4-acetamidomethylbenzoate, the title compound was obtained as whitecrystals, m.p.=103-104° C.

¹H-NMR(CDCl₃)δ: 1.45(3H, d, J=7.3 Hz), 1.93(3H, s), 2.53(1H, br.s),4.63(2H, s), 5.07(1H, dq, J=7.3 Hz), 6.02(1H, br.d, J=7.3 Hz),7.24-7.32(4H, m). MS(EI): 193(M⁺).

(6) Synthesis of (S)-N-(1-(4-Chloromethylphenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 95(4) using(S)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide instead ofN-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide, the title compoundwas obtained as white crystals, m.p.=114-116° C.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=7.3 Hz), 1.98(3H, s), 4.57(2H, s),5.12(1H, dq, J=7.3 Hz), 5.70(1H, br), 7.29-7.38(4H, m). MS(EI): 211(M⁺);[α]_(D) ²⁵-145.0° (c=1.00, CHCl₃).

(7) Synthesis of(S)-N-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine, the title compound was obtained as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 1.97(3H, s), 2.49-2.53(4H, m),3.50-3.54(6H, m), 5.12(1H, dq, J=7.3 Hz), 5.84-5.87(1H, br),6.12-6.16(1H, m), 6.36-6.40(1H, m), 7.25-7.32(4H, m), 7.46-7.55(1H, m).MS(EI): 356(M⁺).

Example 120 Synthesis of(R)-N-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

(1) Synthesis of (R)-N-(1-Phenylethyl)acetamide

By similar reaction and treatment to that in Example 119(1) using(R)-(+)-1-phenylethylamine instead of (S)-(−)-1-phenylethylamine, thetitle compound was obtained as white crystals.

m.p.=100-102° C.; ¹H-NMR(CDCl₃)δ: 1.47(3H, d, J=7.3 Hz), 1.96(3H, s),5.11(1H, dq, J=7.3 Hz), 5.95(1H, br), 7.22-7.36(5H, m). MS(EI): 163(M⁺).

(2) Synthesis of (R)-N-(1-(4-Acetylphenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 119(2) using(R)-1-phenylethylacetamide instead of (S)-1-phenylethylacetamide, thetitle compound was obtained as white crystals, m.p.=125-127° C.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 1.99(3H, s), 2.58(3H, s),5.14(1H, dq, J=7.3 Hz), 6.17(1H, br.d, J=6.6 Hz), 7.39(2H, d, J=7.9 Hz),7.91(2H, d, J=7.9 Hz). MS(EI): 205(M³⁰).

(3) Synthesis of (R)-4-(1-Acetamidoethyl)benzoic Acid

By similar reaction and treatment to that in Example 95(1) using(R)-N-(1-(4-acetylphenyl)ethyl)acetamide instead ofN-(1-(4-acetylphenyl)-1-methylethyl) acetamide, the title compound wasobtained as pale-yellow crystals, m.p.=189-192° C.

¹H-NMR(DMSO-d₆)δ: 1.35(3H, d, J=7.3 Hz), 1.86(3H, s), 4.96(1H, dq, J=7.3Hz), 7.42(2H, d, J=8.6 Hz), 7.91(2H, d, J=7.9 Hz), 8.36(1H, d, J=7.9Hz), 12.85(1H, br.s). MS(EI): 207(M⁺).

(4) Synthesis of Methyl (R)-4-(1-Acetamidoethyl)benzoate

By similar reaction and treatment to that in Example 95(2) using(R)-4-(1-acetamidoethyl)benzoic acid instead of4-(1-acetamido-1-methylethyl)benzoic acid, the title compound wasobtained as white crystals.

m.p.=126-128° C.; ¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=7.3 Hz), 2.00(3H, s),3.91(3H, s), 5.16(1H, dq, J=7.3 Hz), 5.85-5.87(1H, br), 7.36-7.39(2H,m), 7.98-8.01(2H, m). MS(EI): 221(M⁺).

(5) Synthesis of (R)-N-(1-(4-Hydroxymethylphenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(3) using methyl(R)-4-(1-acetamidoethyl)benzoate instead of methyl4-acetamidomethylbenzoate, the title compound was obtained as whitecrystals, m.p.=102-104° C.

¹H-NMR(CDCl₃)δ: 1.44(3H, d, J=6.6 Hz), 1.92(3H, s), 2.67(1H, br.s),4.62(2H, s), 5.06(1H, dq, J=7.3 Hz), 6.09(1H, br.d, J=7.3 Hz),7.23-7.31(4H, m). MS(EI): 193(M⁺).

(6) Synthesis of (R)-N-(1-(4-Chloromethylphenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 95(4) using(R)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide instead ofN-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide, the title compoundwas obtained as white crystals, m.p.=113-114° C.

¹H-NMR(CDCl₃)δ: 1.46(3H, d, J=7.3 Hz), 1.96(3H, s), 4.56(2H, s),5.11(1H, dq, J=7.3 Hz), 5.88(1H, br), 7.28-7.37(4H, m). MS(EI): 211(M⁺);[α]_(D) ²⁵ 145.80° (c=1.00, CHCl₃).

(7) Synthesis of(R)-N-(1-(4-((4-(6-Fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine, the title compound was obtained as a pale-yellow oil.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 1.97(3H, s), 2.49-2.53(4H, m),3.50-3.54(6H, m), 5.12(1H, dq, J=7.3 Hz), 5.90-5.93(1H, br),6.12-6.16(1H, m), 6.36-6.40(1H, m), 7.25-7.32(4H, m), 7.46-7.55(1H, m).MS(EI): 356(M⁺).

Example 121 Synthesis of(S)-N-(1-(4-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=114-115° C.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=6.6 Hz), 1.98(3H, s), 2.57-2.61(4H, m),3.09-3.12(4H, m), 3.54(2H, s), 5.12(1H, dq, J=7.3 Hz), 5.73(1H, br.d,J=7.3 Hz), 6.83-6.98(4H, m), 7.25-7.33(4H, m). MS(EI): 355(M⁺);Elemental analysis: Calculated: C; 70.96, H; 7.37, N; 11.82; Found: C;70.97, H; 7.37, N; 11.76; [α]_(D) ²⁵ −87.0° (c=1.00, CHCl₃).

Example 122 Synthesis of(R)-N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using(R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazinedihydrochloride instead of phenylpiperazine, the title compound wasobtained as white crystals, m.p.=114-115° C.

¹H-NMR(CDCl₃)δ: 1.48(3H, d, J=7.3 Hz), 1.98(3H, s), 2.57-2.61(4H, m),3.09-3.12(4H, m), 3.54(2H, s), 5.12(1H, dq, J=7.3 Hz), 5.72(1H, br.d,J=7.3 Hz), 6.83-6.98(4H, m), 7.25-7.33(4H, m). MS(EI): 355(M⁺);Elemental analysis: Calculated: C; 70.96, H; 7.37, N; 11.82; Found: C;71.03, H; 7.35, N; 11.79; [α]_(D) ²⁵ 87.40 (c=1.00, CHCl₃).

Example 123 Synthesis ofN-(1-(4-(1-(4-(6-fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead ofphenylpiperazine andN-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound can beobtained.

Example 124 Synthesis ofN-(4-(1-(4-(Pyridin-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(2-pyridyl)piperazine instead of phenylpiperazine andN-(4-(1-chloroethyl)phenylmethyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound can beobtained.

Example 125 Synthesis ofN-(1-(4-(1-(4-(6-Fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)methyl)acetamide

By similar reaction and treatment to that in Example 1(5) using1-(6-fluoropyridin-2-yl)piperazine instead of phenylpiperazine andN-((4-(1-chloroethyl)phenyl)methyl)acetamide instead ofN-(4-chloromethylphenylmethyl)acetamide, the title compound can beobtained.

Example 126 Synthesis of(S)-N-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

(1) Synthesis of (S)-4-(1-Aminoethyl)benzoic Acid

By similar reaction and treatment to that in Example 68(2) using(S)-4-(1-acetamidoethyl)benzoic acid obtained in Example 119(3) insteadof 2-(4-methylphenyl)-2-methylpropionitrile, the title compound can beobtained.

(2) Synthesis of Methyl (S)-4-(1-Aminoethyl)benzoate

By similar reaction and treatment to that in Example 95(2) using(S)-4-(1-aminoethyl)benzoic acid instead of4-(1-acetamido-1-methylethyl)benzoic acid, the title compound can beobtained.

(3) Synthesis of methyl(S)-4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)benzoate

By similar reaction and treatment to that in Example 68(13) using methyl(S)-4-(1-aminoethyl)benzoate instead ofN-(4-(1-amino-1-methylethyl)phenylmethyl)acetamide, the title compoundcan be obtained.

(4) Synthesis of(S)-4-(1-(4-Hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 1(3) using methyl(S)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate instead ofmethyl 4-acetamidomethylbenzoate, the title compound can be obtained.

(5) Synthesis of(S)-4-(1-(4-Chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 95(4) using(S)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide, thetitle compound can be obtained.

(6) Synthesis of(S)-4-(1-(4-Azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 59(1) using((S)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of 4-chloromethylacetophenone, the title compound can beobtained.

(7) Synthesis of(S)-4-(1-(4-Aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 68(5) using(S)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of methyl 2-(4-azidomethylphenyl)-2-methylpropionate, the titlecompound can be obtained.

(8) Synthesis of(S)-N-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 68(6) using(S)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of methyl 2-(4-aminomethylphenyl)-2-methylpropionate, the titlecompound can be obtained.

Example 127 Synthesis of(R)-N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

(1) Synthesis of (R)-4-(1-Aminoethyl)benzoic Acid

By similar reaction and treatment to that in Example 68(2) using(R)-4-(1-acetamideethyl)benzoic acid obtained in Example 120(3) insteadof 2-(4-methylphenyl)-2-methylpropionitrile, the title compound can beobtained.

(2) Synthesis of Methyl (R)-4-(1-Aminoethyl)benzoate

By similar reaction and treatment to that in Example 95(2) using(R)-4-(1-aminoethyl)benzoic acid instead of4-(1-acetamido-1-methylethyl)benzoic acid, the title compound can beobtained.

(3) Synthesis of Methyl(R)-4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)benzoate

By similar reaction and treatment to that in Example 68(13) using methyl(R)-4-(1-aminoethyl)benzoate instead ofN-(4-(1-amino-1-methylethyl)phenylmethyl)acetamide, the title compoundcan be obtained.

(4) Synthesis of(R)-4-(1-(4-Hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 1(3) using imethyl(R)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate instead ofmethyl 4-acetamidomethylbenzoate, the title compound can be obtained.

(5) Synthesis of(R)-4-(1-(4-Chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 95(4) using(R)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide, thetitle compound can be obtained.

(6) Synthesis of(R)-4-(1-(4-Azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 59(1) using(R)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of 4-chloromethylacetophenone, the title compound can beobtained.

(7) Synthesis of(R)-4-(1-(4-Aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine

By similar reaction and treatment to that in Example 68(5) using(R)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of methyl 2-(4-azidomethylphenyl)-2-methylpropionate, the titlecompound can be obtained.

(8) Synthesis of(R)-N-(4-(1-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide

By similar reaction and treatment to that in Example 68(6) using(R)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazineinstead of methyl 2-(4-aminomethylphenyl)-2-methylpropionate, the titlecompound can be obtained.

In the same manner as in the above Examples, the following compounds canbe produced.

Example 128N-(4-((4-(1-Methylimidazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

Example 129N-(1-(4-((4-(1-Methylimidazol-2-yl)piperazin-1-yl)methyl)phenyl-1-methylethyl)acetamide

Example 130 N-(1-(4-((4-(1-Methylimidazol-2-yl)piperazin-1-ylmethyl)phenyl)ethyl)acetamide

Example 131 N-(4-(1-(4-(1-Methylimidazol-2-yl)piperazin-1-ylethyl)phenylmethyl)acetamide

Example 132N-(1-(4-(1-(4-(1-Methylimidazol-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide

Example 133N-(1-(4-((4-(1-Methylimidazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide

Example 134N-(4-((4-(5-Methylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

Example 135N-(4-((4-(4-Methylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

Example 136N-(4-((4-(4,5-Dimethylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide

Example 137N-(1-(4-((4-(5-Methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide

Example 138N-(1-(4-((4-(5-Methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

Example 139N-(1-(4-((4-(4-Methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

Example 140N-(1-(4-((4-(4,5-Dimethylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide

Example 141 N-(1-(4-((4-(5-Methylthiazol-2-yl)piperazin-1-ylmethyl)phenyl)cyclopropyl)acetamide

The action and effect of the present invention is explained in moredetail in the following by Experimental Examples.

Experimental Example 1 Effect on TNF-α, IL-10 Production in Mice (InVivo)

To female BALB/c mice (purchased from Japan Charles River) wasintraperitoneally administered LPS (lipopolysaccharide: 500 μg/kg,derived from Escherichia coli 055:B5, manufactured by Difco). Since theTNF-α concentration in serum reaches a peak at 90 min after LPSadministration, the TNF-α concentration in the serum at this point wasmeasured using FACTOR TEST mTNF-α (manufactured by Genzyme) and theIL-10 concentration at the same point of time was also measured usingMurine IL-10 ELISA Kit (manufactured by Endogen). The test compound wasorally administered at 30 min before LPS administration, and the TNF-αconcentration and IL-10 concentration were measured in the same manner.The results are shown in Table 1. The effect of the test compound on theTNF-α production and IL-10 production was calculated by the followingformula as the ratio relative to the test compound non-administrationgroup.

TABLE 1$\frac{{Concentration}\quad {on}\quad {administration}\quad {of}\quad {test}\quad {compound}}{{Concentration}\quad {without}\quad {administration}\quad {of}\quad {test}\quad {compound}} \times 100\quad (\%)$

Example TNF-α production (%) IL-10 production (%) 20 17 770 48 12 888 5116 533 58 19 499 72 20 510 81 11 1035 82 11 742

Experimental Example 2 Effect on TNF-α, IL-10 Production by HumanMonocyte (In Vitro)

Blood is taken from healthy volunteers and monocytes are separated usinga lymphocyte separation medium (Flow Laboratories). The cells aresuspended in RPMI-1640 medium supplemented with 10% FCS (fetal calfserum: manufactured by Gibco). Monocytes (5×10⁶/ml) are stimulated usingLPS (1 μg/ml) and PMA (phorbol 12-myristate 13-acetate, 10 ng/ml,manufactured by Sigma) and incubated with test compounds having variousconcentrations at 37° C. under humid conditions containing 5% CO₂. Afterincubation for 24 hr, the TNF-α concentrations in the supernatant aremeasured using Cytoscreen human TNF-α ELISA Kit (manufactured byBiosource).

Experimental Example 3 Effect on Endotoxin Shock (Life and Death)

To female BALB/c mice (purchased from Japan Charles River) wasintraperitoneally administered LPS (E. coli 055 B5, 10 mg/kg). The testcompound was orally administered at 30 min before LPS administration.The survival of the mice was monitored for 3 days from the next day. Asthe test compound, the compound of Example 20 was used. As a result, allmice in the test compound non-administration group (9 mice per group)died but 8 mice in the test compound administration group (9 mice pergroup) survived, showing markedly significant effect.

Experimental Example 4 Therapeutic Effect on Adjuvant Arthritis

Killed Mycobacterium tuberculosis was inoculated to male Lewis rats(purchased from Seac Yoshitomi, Ltd.) at the tail base to cause adjuvantarthritis. For 6 days from day 15 to day 20 when arthritis wasdeveloped, the test compound was orally administered at 30 mg/kg. Thevolume of the limb was measured with the lapse of time from day 15. Asthe test compound, the compound of Example 20 was used. The changes inthe volume of the limb from day 15 to day 20 were measured. As a result,the volume of the limb increased by 0.344 ml in the test compoundnon-administration rats and decreased by 0.186 ml in the test compoundadministered rats. It was clarified that the inventive compound markedlyinhibited the onset of adjuvant arthritis.

Experimental Example 5 Therapeutic Effect on Collagen Arthritis

Bovine-derived type II collagen (purchased from Koragen gijutsukenkyukai) is intradermally injected twice to DBA/1J mice (purchasedfrom Seac Yoshitomi, Ltd.) at the tail base, together with completeFreund's adjuvant H37Rv (purchased from Wako Pure Chemical Industries,Ltd.) at day 0 and day 21. From day 22 to day 33 after the injection,the test compound is orally administered. The swelling of the joints ofthe four limbs is observed and scored in 0 (no change)—3 (edema of 5fingers). The joint swelling score of each mouse is the total scores ofthe four limbs.

Experimental Example 6 Affinity for Dopamine D₂ Receptor; ³H-spiperoneBinding

Preparation of crude synaptic membranes and a binding test wereperformed according to the method of I. Creese et al. [European Journalof Pharmacology, vol. 46, p. 377 (1977)]. The crude synaptic membraneswere prepared from freeze preserved rat corpus striatum, and themembrane specimen and ³H-spiperone were reacted in the presence of thetest compound at 37° C. for 20 min. After the completion of thereaction, the reaction mixtures were immediately filtered by suction onWhatman GF/B filter (trademark) and the radioactivity on the filter wasmeasured by Top Count. Every reaction was carried out in the presence of100 nM ketanserin. The non-specific binding was determined in thepresence of 100 μM(±)-sulpiride. The 50% inhibition concentration (IC₅₀)of the test compound was calculated by two-point interpolation, fromwhich inhibitory constant (Ki value) was determined.

Experimental Example 7 Affinity for Serotonin 2 Receptor; ³H-ketanserinBinding

Preparation of crude synaptic membranes and a binding test wereperformed according to the method of Leysen J. E. et al. [MolecularPharmacology, vol. 21, p. 301 (1982)]. The crude synapse membranes wereprepared from freeze preserved rat cerebral cortex, and the membranespecimen and ³H-ketanserin were incubated in the presence of the testcompounds at 37° C. for 20 min. After the completion of the reaction,the reaction mixture was immediately filtered by suction on Whatman GF/Bfilter (trademark) and the radioactivity on the filter was measured byTop Count. The non-specific binding was determined in the presence of 10μM ritanserin. The 50% inhibition concentration (IC₅₀) of the testcompound was calculated by two-point interpolation, from whichinhibitory constant (Ki value) was determined.

Experimental Example 8 Affinity for Adrenalin α1 Receptor; ³H-prazosinBinding

Preparation of crude synaptic membranes and a binding test wereperformed according to European Journal of Pharmacology, vol. 55, p. 323(1979). The crude synaptic membranes were prepared from freeze preservedrat cerebral tissue, and the membrane specimen and ³H-prazosin wereincubated in the presence of the test compound at 25° C. for 30 min.After the completion of the reaction, the reaction mixture wasimmediately filtered by suction on whatman GF/B filter (trademark) andthe radioactivity on the filter was measured by Top Count. Thenon-specific binding was determined in the presence of 100 μM WB4101.The 50% inhibition concentration (IC₅₀) of the test compound wascalculated by two-point interpolation, from which inhibitory constant(Ki value) was determined.

Experimental Example 9 Affinity for serotonin 1A receptor; ³H-8-OH-DPATBinding

The specific serotonin 1A (5-HT_(1A)) receptor binding test wasperformed according to the method described in J. Neurochem., 44, 1685(1985). The crude synaptosome fractions were prepared from thehippocampus of 9 to 10-week-old Wistar rats and suspended in 50 mMTris-hydrochloric acid buffer (pH 7.4) containing 1 mM manganesechloride and used for the test. To the synaptosome suspension were addedseveral concentrations of the test compounds and tritium-labeled8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT: final concentration 1 nM)and the mixture was reacted at 37° C. for 12 min. After the completionof the reaction, the reaction mixture was immediately filtered bysuction on Whatman GF/B filter (trademark), the filter was washed with50 mM Tris-hydrochloric acid buffer (pH 7.4) and the radioactivity onthe filter was measured by Top Count. The non-specific binding wasdetermined in the presence of 1 μM WAY-100635. The 50% inhibitionconcentration (IC₅₀) of the test compound was calculated by two-pointinterpolation, from which inhibitory constant (Ki value) was determined.

The results of Experimental Examples 6-9 are shown in Table 2. In theTable, * shows IC₅₀ value.

TABLE 2 Example D₂ 5-HT_(1A) 5-HT₂ α1 20 >1000* >1000* >1000* >1000*48 >1000* >1000* >1000* >1000* 51 >1000* >1000* >1000* >1000*58 >1000* >1000* >1000* >1000* 72 >1000* >1000* >1000* >1000*81 >1000* >1000* >1000* >1000*

Experimental Example 10 Toxicity Test

In a single administration toxicity test, the test compound isadministered to male and female SD rats (3 rats/group) and beagle (1dog/group) and the toxicity by single administration is evaluated usingthe incidence of death, general condition and body weight as indices. Ina repeat administration toxicity test, the test compound is repeatedlyadministered to male and female SD rats (6 rats/group) and male andfemale beagles (2 dogs/group) for 2 weeks and the toxicity by repeatadministration is evaluated using the general condition, body weight,intake, hematological test, blood biochemiocal test, organ weight andautopsy (inclusive of histopathological test) as indices.

Experimental Example 11 Evaluation of Bioavailability in Rats

The test compound is intravenously and orally administered to SD femalerats (5 rats per group). The blood is taken with the lapse of time andthe drug concentration in plasma is measured by High Performance LiquidChromatography. The bioavailability (BA) is calculated by the followingformula. $\frac{\begin{matrix}{{AUC}\quad {on}\quad {oral}} \\{administration}\end{matrix}}{\begin{matrix}{{AUC}\quad {on}\quad {intravenous}} \\{administration}\end{matrix}} \times \frac{\begin{matrix}{{dose}\quad {of}\quad {intravenous}} \\{administration}\end{matrix}}{\begin{matrix}{{dose}\quad {of}\quad {oral}} \\{administration}\end{matrix}} \times 100(\%)$AUC: area under plasma concentration − time curve

Industrial Applicability

As is evident from the above-mentioned pharmacological experiment andvarious experiments, since the compound (I) of the present invention anda pharmaceutically acceptable salt thereof are free of or show onlystrikingly reduced expression of an effect on the central nervoussystem, they have highly safe and superior TNF-α production inhibitoryeffect and/or IL-10 production promoting effect, and are useful for theprophylaxis or treatment of various diseases caused by abnormal TNF-αproduction, diseases curable with IL-10, such as chronic inflammatorydiseases, acute inflammatory diseases, inflammatory diseases due toinfection, autoimmune diseases, allergic diseases, and TNF-α mediateddiseases.

This application is based on application Nos. 280880/1997 and261100/1998 filed in Japan, the contents of which are incorporatedhereinto by reference.

What is claimed is:
 1. A piperazine compound of the formula

wherein R¹ and R² are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substitutedby a group selected from the group consisting of lower alkyl and loweracyl, nitro, hydroxy or cyano; R³, R⁴ and R⁵ are the same or differentand each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino,hydroxy or amino mono- or di-substituted by a group selected from thegroup consisting of lower alkyl and lower acyl; R⁶ and R⁷ are the sameor different and each is hydrogen, lower alkyl, lower alkyl substitutedby 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3halogen(s); R⁸ and R⁹ are the same or different and each is hydrogen orlower alkyl; Y is a group of the formula

wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen orlower alkyl, R¹² and R¹³ are the same or different and each is hydrogenor lower alkyl, or R¹² and R¹³ in combination form alkylene, R¹⁴ and R¹⁵are the same or different and each is hydrogen or lower alkyl, m is aninteger of 0-2, n is an integer of 0-2, and 0≦m+n ≦2; and ring A ispyrimidyl, or a pharmaceutically acceptable salt thereof.
 2. Thepiperazine compound of claim 1, wherein R³, R⁴ and R⁵ are the same ordifferent and each is hydrogen, halogen or lower alkoxy, or apharmaceutically acceptable salt thereof.
 3. The piperazine compound ofclaim 1, which has the following formula

wherein R¹ and R² are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino, amino mono-or di-substitutedby a group selected from the group consisting of lower alkyl and loweracyl, nitro, hydroxy or cyano; ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by agroup selected from the group consisting of lower alkyl and lower acyl,and R¹⁸ is hydrogen or lower alkyl; R⁶ and R⁷ are the same or differentand each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3halogen(s); and Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene, or apharmaceutically acceptable salt thereof.
 4. The piperazine compound ofclaim 1, which has the following formula

wherein R¹ and R² are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substitutedby a group selected from the group consisting of lower alkyl and loweracyl, nitro, hydroxy or cyano; ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino mono- or di-substituted by agroup selected from the gor ip consisting of lower alkyl and lower acyl,and R¹⁸ is hydrogen or lower alkyl; R⁶ and R⁷ are the same or differentand each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3halogen(s); R^(8a) is lower alkyl; and Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R1² and R¹³ in combination form alkylene, or apharmaceutically acceptable salt thereof.
 5. The piperazine compound ofclaim 4, wherein R^(8a) is methyl, or a pharmaceutically acceptable saltthereof.
 6. The piperazine compound of claim 1, which has the followingformula

wherein R¹ and R² are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substitutedby a group selected from the group consisting of lower alkyl and loweracyl, nitro, hydroxy or cyano; ring A′ is a group of the formula

wherein R¹⁶ and R¹⁷ are the same or different and each is hydrogen,halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by agroup selected from the group consisting or lower alkyl and lower acyl,and R¹⁸ is hydrogen or lower alkyl; R⁶ and R⁷ are the same or differentand each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3halogen(s); R^(8a) and R^(9a) are the same or different and each islower alkyl; and Y¹ is a group of the formula

wherein R¹² and R¹³ are the same or different and each is hydrogen orlower alkyl, or R¹² and R¹³ in combination form alkylene, or apharmaceutically acceptable salt thereof.
 7. The piperazine compound ofclaim 6, wherein R^(8a) and R^(9a) are both methyl, or apharmaceutically acceptable salt thereof.
 8. The piperazine compound ofany one of claims 3-7, wherein one of R⁶ and R⁷ is hydrogen and theother is acyl, or a pharmaceutically acceptable salt thereof.
 9. Thepiperazine compound of any one of claims 3-7, wherein R¹² and R¹³ arethe same or different and each is hydrogen or methyl, or R¹² and R¹³ incombination form ethylene, or a pharmaceutically acceptable saltthereof.
 10. The piperazine compound of any one of claims 1, 2, and 3,which is a member selected from the group consisting ofN-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide,N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-formamide,N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-propionamide,and N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-phenyl)cyclopropyl)acetamide,or a pharmaceutically acceptable salt thereof. 11.N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-phenyl)cyclopropyl)acetamide, or a pharmaceutically acceptablesalt thereof.
 12. The piperazine compound of claim 2, wherein one of R⁶and R⁷ is hydrogen and the other is acyl, or a pharmaceuticallyacceptable salt thereof.
 13. The piperazine compound of claim 2, whereinR¹² and R¹³ are the same or different and each is hydrogen or methyl, orR¹² and R¹³ in combination form ethylene, or a pharmaceuticallyacceptable salt thereof.
 14. The piperazine compound of claim 8, whereinR¹² and R¹³ are the same or different and each is hydrogen or methyl, orR¹² and R¹³ in combination form ethylene, or a pharmaceuticallyacceptable salt thereof.
 15. The piperazine compound of any one ofclaims 1, 2-7, 11, and 12-14 herein the pharmaceutically acceptable saltis selected from the group consisting of salts of hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid,citric acid, succinic acid, tartaric acid, malic acid, mandelic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and10-camphorsulfonic acid.
 16. The piperazine compound of claim 10,wherein the pharmaceutically acceptable salt is selected from the groupconsisting of salts of hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleicacid, fumaric acid, benzoic acid, citric acid, succinic acid, tartaricacid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, and 10-camphorsulfonic acid.
 17. Thepiperazine compound of claim 11, wherein the pharmaceutically acceptablesalt is selected from the group consisting of salts of hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid,citric acid, succinic acid, tartaric acid, malic acid, mandelic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and10-camphorsulfonic acid.
 18. The piperazine compound of claim 10, whichisN-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamideor a pharmaceutically acceptable salt thereof.
 19. The piperazinecompound of claim 18, wherein the pharmaceutically acceptable salt is asalt of hydrochloric acid.
 20. A pharmaceutical composition containingthe piperazine compound of any one of claims 1, 2-7, 11, 18, and 19, ora pharmaceutically acceptable salt thereof, as an active ingredient. 21.The piperazine compound of claim 20, wherein the pharmaceuticallyacceptable salt is selected from the group consisting of salts ofhydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid,benzoic acid, citric acid, succinic acid, tartaric acid, malic acid,mandelic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and 10-camphorsulfonic acid.
 22. Apharmaceutical composition containing the piperazine compound of claim10, or a pharmaceutically acceptable salt thereof, as an activeingredient.